Antiepileptic Drugs, 5th Edition

Felbamate

27

Felbamate

John M. Pellock MD*

James L. Perhach PhD, FCP**

Duane R. Sofia PhD***

* Chairman, Division of Child Neurology, Professor of Neurology, Pediatrics, Pharmacy, and Pharmaceutics, Medical College of Virginia; Hospitals and Physicians, Virginia Commonwealth University Health Care Systems, Richmond, Virginia

** Senior Director, Clinical Pharmacology, Perdue Pharma L.P., Princeton, New Jersey

*** Vice President, Department of Preclinical Research, Wallace Laboratories, Cranbury, New Jersey

Felbamate (FBM), a dicarbamate compound related to meprobamate, was initially synthesized in the 1950s. Because it had no tranquilizing or sedative activity, FBM was not initially developed until 1986, when efficacy in a wide range of seizure models was reported (1). FBM was synthesized and developed by Wallace Laboratories (Cranbury, NJ) and became the first of the “new-generation” antiepileptic drugs (AEDs) approved for marketing in the United States in 1993. Its clinical success as a potent, broad-spectrum AED is well documented, but the appearance of life-threatening idiosyncratic reactions has markedly reduced its use to a third- or fourth-line agent for use in patients with refractory epilepsy.

The 1995 fourth edition of Antiepileptic Drugs dedicated six chapters to this novel AED (2, 3, 4, 5, 6, 7), discussing modes of action, chemistry and biotransformation, pharmacokinetics, FBM drug interactions, clinical use, and toxicity. The current chapter summarizes those writings and offers updates, particularly regarding clinical use and toxicity.

ANTICONVULSANT ACTIVITY

The anticonvulsant effects of FBM were evaluated by Swinyard et al. (1) against maximal electroshock seizure (MES) and subcutaneous Metrazol (s.c.MET) tests, where the drug was administered to mice and rats by the oral route (Table 27.1). FBM protected mice against MES with a resultant median effective dose (ED50) of 81 mg/kg. The oral ED50 in the MES tests in rats was 48 mg/kg. FBM also was effective against chemically induced convulsions. The oral ED50s in the s.c.MET test were 548 and 238 mg/kg in mice and rates, respectively (2).

FBM demonstrated a high degree of safety in mice and rats as measured by neurotoxicity and calculated protective indices (PI). The median toxic dose (TD50) in mice from the rotorod test was 1,545 mg/kg (Table 27.1) after oral dosing. In the rat, the oral TD50 was estimated at >3,000 mg/kg (Table 27.1). Compared with phenytoin (PHT), carbamazepine (CBZ), phenobarbital, and valproic acid (VPA), FBM demonstrated the lowest potential for neurotoxicity (i.e., the highest TD50 value). Thus, protective indices (TD50/ED50) for FBM after oral administration to mice and rats provide for a significantly large margin of safety or, in other words, a very wide therapeutic window (2).

The anticonvulsant effects of FBM were further substantiated in kindling models of epilepsy using cornea- and amygdala-kindled rats (8). In pentylenetetrazol-kindled rats, FBM significantly reduced the intensity of behavioral seizures, and seizure frequency was reduced in monkeys made chronically epileptic by injections of aluminum hydroxide (9). There was a marked increase in seizure rate when FBM was withdrawn. Yamaguchi and Rogawski (10) also have shown that FBM was effective in protecting mice against 4-aminopyridine-induced seizures, using lethality as the end point. These findings are consistent with the ability of FBM to inhibit seizure spread. FBM also was effective in two models of status epilepticus in the rat (11).

Interactions, Safety, and Neuroprotection

The ability of FBM to enhance the anticonvulsant activities of PHT, VPA, CBZ, phenobarbital, and diazepam, and, conversely, the effects of these drugs on the anticonvulsant action of FBM, were evaluated in mice. Initial experiments showed that FBM enhanced the protective effects of diazepam, PHT, VPA, and CBZ in the MES test. Based on early data (2), it is apparent that a positive interaction often

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occurs between FBM and standard AEDs in laboratory animal seizure models. The results of the safety pharmacology studies with FBM clearly point to its excellent safety profile in various body systems (2).

TABLE 27.1. PROFILE OF ANTICONVULSANT ACTIVITY OF ORALLY ADMINISTERED FELBAMATE AND PROTOTYPICAL ANTIEPILEPTIC DRUGS IN MICE AND RATSa

 

Mice

Rats

   

MES

s.c. MET

 

MET

s.c. MET

Substance

TD50b (mgkg)

ED50 (mgkg)

PIc

ED50 (mgkg)

PIc

TD50 (mgkg)

ED50 (mgkg)

PIc

ED50 (mgkg)

PIc

Felbamate

1,545.0 (1,299.1-1,986.9)

81.1 (72.0-92.8)

19.1

548.2 (433.7-750.7)

2.8

>3,000.0

47.8 (41.0-57.3)

>63

238.1 (132.1-549.3)

>12

Phenytoin

86.7 (80.4-96.1)

9.0 (7.40-10.6)

10.0

No protection

NE

>3,000.0

29.8 (21.9-38.9)

>100

No protection

NE

Carbamazepine

217.2 (131.5-270.1)

15.4 (12.4-17.3)

14.0

48.1 (40.8-57.4)

4.5

813.1 (488.8-1,233.9)

8.5 (3.4-10.5)

95.7

No protection

NE

Phenobarbital

96.8 (79.9-115.0)

20.1 (14.8-31.6)

4.8

12.6 (8.0-19.1)

7.7

61.1 (43.7-95.9)

9.1 (7.6-11.9)

6.7

11.5 (7.7-15.0)

5.3

Valproic acid

1,264.4 (800.0-2,250.0)

664.8 (605.3-718.0)

1.9

388.3 (348.9-438.6)

3.3

280.2 (191.3-352.8)

489.5 (351.1-728.4)

0.6

179.6 (146.7-210.4)

1.6

MES, maximal electroshock seizure test; s.c. MET, subcutaneous Metrazol seizure threshold; TD50, median toxic dose; ED50, median effective dose; NE, not evaluable.

aValues in parentheses are 95% confidence limits.

b Toxic dose (rotorod performance).

c Protective index (TD50/ED50).

From Swinyard EA, Sofia RD, Kupferberg HJ. Comparative anticonvulsant activity and neurotoxicity of felbamate and four prototype antiepileptic drugs in mice and rats.Epilepsia 1986;27:27-34, with permission.

The neuroprotective effect of FBM was shown in vitro by inhibition of hypoxic injury in a hippocampal slice (12) and in vivo by Wasterlain et al. in a neonatal rat model (13). Moreover, posthypoxic treatment with FBM in this same model produced both dose-dependent and time-dependent neuroprotective effects (14). A neuroprotective effect of FBM also was observed after kainic acid-induced status epilepticus (15) and suggested that FBM had no adverse effects on learning and memory.

Mechanism of Action

Although the precise mechanism of action for the anticonvulsant and neuroprotective effects of FBM has not been fully elucidated, several hypotheses have been proposed and tested to suggest four potential mechanisms, all antiexcitatory (2,16).

FBM interferes with voltage-gated sodium channels, resulting in the blockade of sustained, repetitive neuronal firing and prevention of seizure spread (8). It indirectly antagonizes N-methyl-D-aspartate (NMDA) by interfering with the binding of glycine to strychnine-insensitive glycine receptors (17). Because glycine acts as an obligatory coagonist for glutamate acting at the NMDA receptor subtype, glycine blockage therefore may lead to a reduction of NMDA receptor-modulated cationic conductance. FBM has no direct NMDA receptor blocking action (2). A third mechanism involves non-NMDA excitatory amino acid receptors. FBM protects against seizures induced by quisqualate and kainate (8) and those induced by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), the natural agonist for these receptor subtypes (18). FBM also inhibits voltage-activated calcium currents at clinically relevant concentrations (19). This may inhibit release of excitatory neurotransmitters and also explain FBM's antiabsence effect.

FBM probably does not substantially affect inhibitory neurotransmission (16). It does not bind to γ-aminobutyric acid (GABA), benzodiazepine, or picrotoxin sites on the GABAA-chloride ionophore complex, and does not affect chloride influx, with or without the presence of GABA (20). Although GABA-potentiating action has been suggested (21), millimolar concentrations are required, whereas the antiexcitatory mechanisms require only the micromolar concentrations of FBM readily achievable in the brain with clinical doses (2).

CHEMISTRY

Felbamate (Felbatol; Wallace Laboratories) is the generic name for 2-phenyl-1,3-propanediol dicarbamate, with the empiric formula C11H14N2O4 and a molecular weight of 238.24 (the conversion factor from concentration to molarity is 1,000/238.24 = 4.20) (3) (Figure 27.1).

 

FIGURE 27.1. Felbamate structure.

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A molecule of FBM is composed of a phenyl ring attached to the middle carbon of the 1,3-propanediol chain. The two hydrogens of the aliphatic primary hydroxyl groups are replaced by a carbamyl group, CONH2. This leads to a symmetric, achiral, nonionic substance with medium lipophiliciry and a high degree of hydrophobicity.

PHYSICOCHEMICAL PROPERTIES

The melting point determined for various commercial-scale lots of drug by differential scanning calorimetry ranged 149.5°C to 150.8°C; FBM reference standard of 99.9% purity had a melting point of 150.3°C to 151.2°C. The solubility of FBM is very low in water and relatively low in common organic solvents. The drug has good solubility only in solvents with strong hydrogen bonding capability to break up the intermolecular hydrogen bonds of FBM in its crystal lattice, such as dimethylsulfoxide or dimethylacetamide. The partition coefficients reveal medium lipophilicity of FBM. This important property allows the drug to cross cell membranes easily and manifests itself in the drug's distribution throughout tissues and organs.

Chemical stability studies of aqueous FBM solutions at acidic to neutral pH indicate that it is relatively stable. In the presence of 0.4 N hydrochloric acid at 40°C, only 1.3% of FBM was hydrolyzed after 24 hours. However, at alkaline pH, the carbamate groups underwent hydrolysis. Treatment with 0.01 N sodium hydroxide for 24 hours at 40°C hydrolyzed 28.9% of the drug; among the hydrolysis products, 19% consisted of the monocarbamate (MCF) and 1.8% of the 2-phenyl-1,3-propanediol. FBM solutions also exhibited considerable stability to oxygenation; bubbling of oxygen through a solution at 40°C for 24 hours led to a loss of 2.4%. When kept at 37°C for 24 hours in human plasma or simulated gastric and intestinal fluid, no significant change could be detected.

BIOTRANSFORMATION

Structurally, FBM is a relatively simple molecule and as such it undergoes only a few enzymatic biotransformation reactions (i.e., hydroxylations of the aromatic phenyl ring or the aliphatic C-2 on the propanediol chain or hydrolysis of the carbamate groups). These primary hydroxy metabolites then are conjugated in secondary biotransformation steps (phase II reactions with glucuronic acid) or, in the case of the primary alcohol hydroxy groups, oxidized further. The conjugation of FBM itself also is possible because a N-glucuronide conjugate of meprobamate has been reported (22). Because the solubility of FBM in aqueous biologic fluids is very low, the aforementioned metabolic reactions would permit the drug to be eliminated in the form of more water-soluble products. Pharmacokinetic studies in animals (23) and humans (24) have indicated that, indeed, the main route of excretion for both FBM and its metabolites is the urine; much less is excreted in the feces.

However, in none of the species studied so far is FBM completely metabolized; a significant amount of drug is excreted unchanged, pointing to a low first-pass effect. The structures of the identified and hypothesized metabolites of FBM are shown in Figure 27.2.

Animal Metabolites

The biotransformation of FBM in rats, rabbits, and dogs has been studied with [14C]FBM as tracer (25). Three metabolites were isolated from rat or dog urine and the isolated compounds positively identified by their high-performance liquid chromatography (HPLC) retention times and mass spectra in the EI and CI mode compared with synthetic reference standards of the metabolites (26). In addition to their identification, 14C HPLC profiles of the metabolites and unchanged drug were obtained for urine and bile of the three species and for plasma of dogs and rats and feces of dogs. Because a pharmacokinetic study with [14C]FBM in these species (27) showed that up to one-third of the 14C in plasma is accounted for by metabolites, 14C metabolic profiling in dog and rabbit plasma also was performed. Approximately 6% or less of the 14C was in the form of the para-hydroxyfelbamate (pOHF) and 2-hydroxyfelbamate (2OHF) metabolites, but the low concentration of 14C in the plasma samples precluded a more accurate balance for metabolites. The amount of unchanged drug in plasma varied from 72% to 100%. The major portion of the urinary 14C was accounted for by the unchanged drug and the pOHF, 2OHF, and MCF metabolites; the remaining 14C was in the form of polar, water-soluble compounds, including conjugates. Because urine is the major route of 14C excretion, the urinary 14C metabolic profiles represent a good overall picture of FBM biotransformation. The rat appears to have the most active metabolism of FBM, in which the formation of the pOHF metabolite predominates. In the rabbit and dog, less of the dose is metabolized and the two hydroxy metabolites are formed in approximately equal amounts, with small amounts of the hydrolysis product MCF also present.

The amount of 14C excreted in feces was smaller than in urine. The 14C in dog feces was composed of the two hydroxy metabolites with a pOHF/2OHF ratio of approximately 1.4, accounting for 60% to 70% of the 14C; that accounted for by unchanged drug varied from 15% to 29%. This indicates that some biliary excretion of the metabolites in free or conjugated form must occur. Studies in bile duct-cannulated rats or dogs dosed with [14C]FBM confirmed the existence of hepatobiliary recirculation of FBM and its metabolites. After enzyme hydrolysis with glucuronidase/sulfatase, up to half of the 14C in the bile of rats collected at 2 hours was pOHF and only 3% was 20HF. In

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dog bile collected at 48 hours, 40% was pOHF and 25% 20HF, and in rabbit bile at 72 hours, 24% was pOHF and 11% was 20HF. In all the bile samples, unchanged FBM accounted for less than 10% of the biliary 14C.

 

FIGURE 27.2. Metabolic pathway.

The sum of all conjugated 14C metabolites in animal urine was estimated based on the solvent-extractable 14C before and after enzymatic hydrolysis with β-glucuronidase/sulfatase. It ranged from 20% to 35% in rat urine, 20% to 30% in rabbit urine, and 10% to 20% in dog urine. The amounts of conjugated metabolites in native bile were estimated at 50% for the rat, 15% for the rabbit, and 70% for the dog. No conjugates were observed in dog feces.

There is no indication of a significant degree of extrahepatic biotransformation of FBM, but more detailed studies of metabolism in animal tissues have not been carried out. Cornford et al. (28) could not detect FBM metabolites in the brain tissue of mice at 5 minutes after an intracarotid injection of 4 mg/kg [14C]FBM. A tissue distribution study in rats dosed with 100 mg/kg [14C]FBM demonstrated extensive distribution of 14C to all tissues (29). In a separate study, the concentration of FBM and its metabolites was determined in rat brain and cerebrospinal fluid (CSF) (AD) and heart tissue (Wallace Laboratories, unpublished data). In rats after a single oral dose of 500 mg/kg, only the 2OHF metabolite was present

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in measurable concentrations in plasma [maximal concentration (Cmax) 7.8 µg/mL], brain and CSF (Cmax 2.7 µg/g), and heart tissue (Cmax 6.6 µg/g). The presence of the metabolites at these low concentrations is of limited importance because the anticonvulsant activity of the metabolites in the rat model is much lower than that of FBM.

Human Metabolites

The biotransformation of FBM in male volunteers dosed with a single dose of 100 or 1,000 mg [14C]FBM has been studied by 14C metabolic profiling in plasma and urine using HPLC ultraviolet and 14C monitoring (30). In plasma samples from both groups, FBM accounted for most of the 14C, but actual metabolite concentrations were too low to be accurately determined. The highest urinary 14C excretion rates were observed during the 4- to 8- and 8-to 1-hour periods. Approximately 50% of the urinary 14C was unchanged drug; the sum of the two hydroxy metabolites accounted for another 10% to 15%, with the pOHF/2OHF ratio in hydrolyzed urine equal to 1.8. The MCF metabolite amount varied from 0.7% to 2.7%, and the remaining 14C was in the form of polar unidentified components. Hydrolysis of the urine with β-glucuronidase/sulfatase caused a decrease in this polar fraction by 16%; this amount probably represents glucuronides or sulfate esters of the three metabolites and the N-glucuronide of FBM. The polar fraction of the urinary 14C remaining after enzyme hydrolysis of the conjugates (25.8% of 14C) has been examined in attempts to identify additional metabolites (31). Mass spectrometry analysis and HPLC comparison with a synthetic reference positively identified the major component of the polar fraction as 3-carbamolyoxy-2-phenylpropionic acid (CPPA) in the free form (Figure 27.3 for structure). This metabolite, accounting for approximately 12% of the urinary 14C in a 4- to 8-hour urine sample, is most likely formed by the oxidation of the MCF metabolites. The percentage indicates that enzyme hydrolysis of FBM to MCF is a major biotransformation pathway in humans. The presence of CPPA in dog urine also has been confirmed.

 

FIGURE 27.3. Felbamate concentration versus dose.

Further research has led to a hypothesis that the FBM metabolite, monocarbamate alcohol, undergoes stepwise oxidation to acid carbamate through an aldehyde intermediate, aldehyde carbamate, and that this aldehyde either is in a dynamic equilibrium with cyclic carbamate or is nonenzymatically converted to atropaldehyde (32). The conjugation and elimination of atropaldehyde would appear to be routine in patients with adequate stores of glutathione (33). This hypothesis further suggested that atropaldehyde might be biologically reactive and could contribute to the toxicity seen in some patients treated with FBM (Figure 27.2).

Evidence to support the formation of the cyclic carbamate intermediate metabolite, 4-hydroxy-5-phenyl tetrahydro-1,3-oxazin-2-one, from MCF and its metabolism to CPPA has been demonstrated in vitro using human liver S9 fractions and microsomes (34)

Sex and Age Differences in Biotransformation

Age but not sex has a significant effect on the pharmacokinetics of FBM in rats (29) and dogs (35,36). To explain those differences in the 14C metabolic profile in urine and feces of 5-week-old and adult dogs has been determined by HPLC (35). Although no qualitative differences in the 14C profiles were apparent, the amount of FBM metabolized in the very young dogs was approximately twice that in adults. The increase was distributed evenly between the two hydroxy metabolites and the polar fraction, and the pOHF/2OHF ratio did not change much.

In a tissue distribution study in adult and neonatal Sprague-Dawley rats dosed with 500 mg/kg [14C]FBM, a more dramatic difference in kinetics and biotransformation was observed (29). Large quantitative differences in plasma 14C profiles were apparent. The plasma concentrations of 2OHF in neonatal rats at peak time were 10-fold higher than in adults, but the pOHF metabolite concentrations were only slightly lower. Brain concentrations of 2OHF in the study showed the same trend: In adults the Cmax at 12 hours was 2.7 µg/g, in neonates at 16 hours it was 54.4 µg/g.

Species Differences in Biotransformation

Based on urinary 14C metabolic profiles of enzyme hydrolyzed urine, no large differences in FBM metabolism between species have been observed. The urine is the major excretion route in all species.

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With regard to phase II metabolic reactions, there appears to be a species difference in the extent of conjugation for each of the three metabolites. This is based on the indirect estimation of the amount of conjugates in the urine before and after hydrolysis with β-glucuronidase/sulfatase (Wallace Laboratories, unpublished data). Approximately 40% of the amount of the pOHF metabolite is conjugated in the rat, 30% in the dog, and 35% in the rabbit. In the case of the 2OHF metabolite, 20% is conjugated in the rat and rabbit and 50% in the dog. The relatively small amounts of the MCF metabolite in urine appear to be approximately 75% in conjugated form in both rabbit and dog urine. The existence of the N-glucuronide of FBM in animal urine is not supported by data; however, in human urine the difference in the amount of FBM before and after enzymatic hydrolysis does indicate the presence of the N-glucuronide.

Induction of the Rat Hepatic Cytochrome P450 System

FBM was found to be a mild rat hepatic cytochrome P450 (CYP) inducer. In male Sprague-Dawley rats dosed daily with 1,000 mg/kg FBM for 5 days, the total CYP isozyme content was increased twofold compared with untreated animals. The drug was found to be approximately 25 times less potent than the standard inducing agent, sodium phenobarbital (37). The capacity of FBM for autoinduction of metabolism in the rat was demonstrated by in vitro incubations with rat hepatic microsomes from animals pretreated with FBM (38) in which, similar to microsomes in phenobarbital-pretreated rats (see section on in vitro biotransformation), the amount of drug metabolized doubled from 10% to approximately 20% to 25%, with the increase exclusively in the amount of the 2OHF metabolite.

CONVERSION

Conversion factor:

Conversion:

(µg/mL) × 4.20 = µmol/L

(µmol/L) ÷ 4.20 = µg/mL

ABSORPTION, DISTRIBUTION, AND EXCRETION

Absorption

FBM is well absorbed after oral administration. This assessment of absorption was obtained from an open-label, parallel study using a single dose of [14C]FBM administered orally to six healthy male subjects (30). Three subjects ingested approximately 100 mg and the other three ingested 1,000 mg of FBM labeled with approximately 80 to 85 µCi of 14C. After oral administration of 100 or 1,000 mg [14C] FBM, over 90% of each 14C dose was recovered in the urine, with less than 5% in the feces. Plasma FBM concentrations paralleled and were only slightly less than the 14C-labeled concentrations. For both 14C and FBM, plasma concentrations increased proportionately with the dose.

Single-Dose Studies

In one study, single oral doses of 100, 200, 400, 600, or 800 mg of FBM or placebo were administered to five different groups of male subjects under double-blind conditions (39). In another study, single doses of 1,200 mg of FBM were administered to eight male subjects (40). Plasma samples were assayed for FBM by a specific HPLC method (41).

Based on AUC0 (area under the plasma concentration-time curve) and Cmax data, plasma FBM concentrations increased proportionally after administration of single doses of 100 to 1,200 mg (Figure 27.3). No evidence of nonlinearity was detected over the dose range studied. The mean ± standard deviation (SD) apparent clearance after a single 1,200 mg dose of FBM as a solution was 25.8 ± 2.9 (mL/hr)/kg.

The absorption of the commercial FBM suspension and tablets has been determined to be bioequivalent to the FBM capsules used in the clinical development of FBM. The absorption rate is similar for all formulations tested, although more rapid for the solution and capsules. The extent of absorption was the same for all dosage forms. The tablet and suspension are absorbed with peak times of 2 to 6 hours.

Multiple-Dose Studies

The steady-state pharmacokinetics and dose proportionality of FBM after oral administration of 400, 800, 1,200, 2,400, and 3,600 mg/day were evaluated in healthy men (400, 800, and 1,200 mg/day) and in newly diagnosed or untreated subjects with epilepsy (42,43). Ten otherwise healthy female subjects with epilepsy participated in the latter study. After 2 weeks at each dosage level, plasma samples were obtained and assayed (41). FBM Cmax, Cmin (trough), and AUCτ were proportional to dose. Multiple daily doses of 1,200, 2,400, and 3,600 mg/day gave Cmin values of 30 ± 5, 55 ± 8, and 83 ± 21 µg/mL, respectively. In a separate dose proportionality study, subjects who had received other AEDs chronically and then converted to 3,600 mg/day of FBM were shown to tolerate doses of FBM up to 6,000 mg/day (44). After 3,600, 4,200, 4,800, 5,400, and 6,000 mg/day of FBM, mean steady-state Cmin(trough) FBM

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concentrations of 87.5, 100.0, 118.6, 122.3, and 134.3 µg/mL, respectively, were observed. Proportional increases in AUCτ also were observed. Time to Cmax did not differ. Food, antacids, and sex of the patient do not effect the pharmacokinetics of FBM (45,46).

Effects of Age

FBM gave dose-proportional steady-state plasma concentrations of 17, 32, and 49 µg/mL in children 4 to 12 years of age at doses of 15, 30, and 45 mg/kg/day, respectively (47). The plasma concentration of FBM in children (≤12 years of age) receiving 45 mg/kg/day is less than the FBM plasma concentration in adults receiving a comparable FBM dosage.

Effect of Renal Impairment

Subjects with four levels of renal dysfunction [creatinine clearance >80 mL/min (normal), >30 to 80, >10 to 30, or 5 to 10 mL/min] were administered a single oral dose of 1,200 mg FBM. Compared with control subjects, apparent total-body clearance, renal clearance, and urinary excretion of FBM were decreased, and half-life, Cmax, and AUC values were increased in subjects with renal dysfunction. Renal clearance of FBM accounted for approximately 30% of apparent total body clearance in the control group and from 9% to 22% in the patients with renal failure. Renal clearance of FBM was significantly correlated with creatinine clearance (R2 = 0.75; p < .001). These data suggest that initial dosage and titration of FBM may require adjustment in patients with renal dysfunction (48).

Distribution

Protein Binding

FBM is the predominant plasma species after oral administration. Binding of FBM to human plasma protein was independent of FBM concentrations between 10 and 310 µg/mL. Binding ranged from 22% to 25%, was mostly to albumin, depended on albumin concentration, and did not alter the protein binding of other AEDs (49).

Tissue Distribution

After administration of a single 100 mg/kg dose of [14C] FBM (~50 µCi) to male rats, peak concentrations were reached and maintained from 2 to 4 hours. Tissue concentrations at 2, 4, 8, 24, and 48 hours after dosing indicated a broad dispersal of FBM across major organs, including liver, kidney, heart, lung, spleen, muscle, gonads, eyes, and brain. Peak brain concentration was observed at 4 hours, but was nearly at maximum at 2 hours. No accumulation of 14C occurred in any of the individual tissues, based on peak 14C levels at 48 hours. Disappearance of FBM from the brain paralleled that from the plasma (50). Similar uniform distribution was observed in pregnant female rats and fetal tissue. Autoradiographic analyses of frozen brain sections of rats suggested that FBM distributes relatively uniformly throughout the brain (51).

Cornford et al. have shown that FBM extraction in a single transcapillary passage was 5% to 20%, and drug uptake in rat brain was not concentration dependent (51). FBM is moderately lipophilic, and lipid-mediated blood-brain barrier penetration of FBM is similar to that of PHT and phenobarbital. Plasma protein does not affect FBM's entry into the brain. Erythrocyte-borne FBM also may supply the brain.

Although no systemic evaluation has been conducted, brain FBM concentrations in humans have been reported to be approximately 0.6 to 0.7 those of plasma. These data are somewhat confounded by the absence of precise plasma collection methods and the presence of other AEDs (52). The distribution ratio of [14C] FBM between red blood cells and plasma or saline was found to be 0.97 to 0.99 (40). Comparable results were observed with dog whole blood and red blood cell suspensions in saline. The distribution and binding to red blood cells was reversible. FBM has been detected in human milk. No data on FBM's presence in saliva or tears are available.

Volume of Distribution

Preclinical data indicated that FBM is relatively uniformly distributed in the body tissues. Data from humans indicate that the apparent volume of distribution is 756 ± 82 mL/kg after a 1,200-mg dose in adults. The volume of distribution in monkeys after intravenous administration of 25 mg/kg was 930 mL/kg.

Elimination and Excretion

After oral administration, FBM concentrations parallel and are only slightly less than those of radioactivity. Approximately 40% to 50% of the absorbed dose (1,000 mg of [14C]FBM) appears unchanged in unhydrolyzed urine, and an additional 52% to 58% is present as metabolites and conjugates (53). Similar profiles of elimination have been observed in rats, rabbits, and dogs (13). In hydrolyzed human urine, approximately 8% to 14% is present as pOHF, 4% to 6% as 2OHF, and 1% to 4% as FBM monocarbamate. None of these has significant anticonvulsant activity. These same metabolites were seen in urine from laboratory animals receiving FBM (35).

Clearance

The clearance of FBM from plasma is independent of the dose of FBM. The mean ± SD apparent clearances for

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healthy volunteers were 36.9 ± 17.7, 38.2 ± 16.8, and 27.6 ± 6.9 (mL/hr)/kg for FBM doses of 400, 800, and 1,200 mg/day. For subjects with newly diagnosed epilepsy, it ranged from 26.8 ± 4.0 to 30.1 ± 7.8 (mL/hr)/kg for FBM doses of 1,200 to 3,600 mg/day (48). For subjects with epilepsy converted from other AEDs, FBM's clearance ranged from 31.7 ± 9.2 to 32.1 ± 6.8 (mL/hr)/kg after administration of 4,200 to 6,000 mg/day (44).

Half-Life

Mean terminal elimination half-lives for radioactivity and FBM ranged from 16 to 22 hours regardless of dose (53). Comparable half-lives were observed for healthy male subjects receiving a 1,200-mg dose of FBM (39). Early reports of a shorter half-life are related to the fact that these subjects were not receiving FBM monotherapy and samples were not collected for a sufficient time (54).

INTERACTIONS WITH OTHER DRUGS

Prediction of Interactions Based on In Vitro Studies

In vitro studies show that FBM is a substrate for CYP3A4 and CYP2E1. Compounds that induce CYP3A4 (e.g., CBZ, PHT, and phenobarbital) increase FBM clearance. However, the CYP3A4 inhibitors gestodene, ethinyl estradiol, and erythromycin have little or no effect on FBM trough plasma concentrations, consistent with the fact that the pathway is relatively minor for FBM under normal (noninduced) conditions.

FBM has been shown in vitro to inhibit CYP2C19, which would account for its effect on PHT clearance, and it has been postulated that this could be the mechanism underlying the reduced clearance of phenobarbital by FBM.

Although not yet examined in vitro, FBM appears to induce the activity of CYP3A4, which would account for its reducing plasma concentrations of CBZ or the progestin gestodene (55).

Effect of Felbamate on Other Antiepileptic Drugs

Phenytoin

During a late phase I trial (54) and subsequent clinical trials, investigators (56, 57, 58, 59) identified an interaction on coadministration of FBM and PHT that resulted in an increase in PHT concentrations, necessitating a decrease in PHT dose.

Further clarification of the effects of FBM on the pharmacokinetics of PHT was sought by Sachdeo et al. (60) in an open-label, rising FBM dose (1,200, 1,800, 2,400, 3,600 mg/day) study in 10 patients with epilepsy (5 men, 5 women, 19 to 50 years of age). Patients were established on PHT monotherapy (200 to 500 mg/day) for a minimum of 2 weeks. Only one PHT dosage adjustment of approximately 20% was permitted during the study. This occurred after the development of signs and symptoms associated with PHT toxicity. Patients then were grouped according to when the dose of PHT was reduced, as well as how many FBM dose increments they completed.

FBM caused an increase in the steady-state plasma concentrations of PHT that was observed at a dose as low as 1,200 mg/day of FBM. Overall (10 patients), the mean steady-state trough plasma concentration of PHT increased from a baseline value of 17 ± 5 µg/mL to 21 ± 5 µg/mL after 1,200 mg/day of FBM, a mean increase of 24%. In six patients whose FBM dose was further increased to 1,800 mg/day, an additional increase in PHT trough concentrations of approximately 20% was observed. Three patients completed the study at 3,600 mg/day of FBM with one PHT dosage reduction before the increase in FBM dose to 2,400 mg/day. Their trough PHT concentration increased from 17 ± 2.9 µg/mL at baseline to 24 ± 3.7 µg/mL when the FBM dose was increased from 1,200 to 1,800 mg/day. The concentration fell to 22.7 ± 4.5 µg/mL when the PHT dose was reduced by 20% and 2,400 mg/day of FBM was administered. The trough concentration increased to 26.4 ± 4.1 µg/mL when the FBM dose was increased to 3,600 mg/day. PHT maximal plasma concentrations and AUCs exhibited parallel increases. Based on these observations, the following dosage recommendations have been formulated: On initiation of therapy with FBM at 1,200 mg/day, an initial PHT dose reduction of approximately 20% is suggested. Subsequent reductions in the PHT dose on implementation of further increases in the FBM dose should be individualized and based on clinical signs, symptoms, and plasma PHT concentrations.

The plasma protein binding of PHT was virtually unchanged (>91%) after FBM administration. The increases in PHT concentrations depended on FBM concentration and dose, suggesting that FBM inhibited PHT metabolism. (The mechanism of this interaction is discussed in the chapter on mechanistic aspects of PHT interactions.)

Valproic Acid

The effects of coadministration of FBM on the disposition of VPA were studied in a randomized, three-period, crossover study in patients with epilepsy previously stabilized on VPA monotherapy (9.5 to 26.2 mg/kg/day) (61). A baseline period, when only VPA was administered, was followed by a two-period crossover, during which patients randomly received a daily dose of either 1,200 or 2,400 mg FBM for a period of 2 weeks.

Nausea and headache were the most common adverse events reported. Coadministration of 1,200 and 2,400 mg/day of FBM increased the mean (± SD) AUC for VPA from a baseline value of 802 ± 174 to 1,025 ± 207 and to

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1,236 ± 290 µg/hr/mL, respectively (increases of 28% and 54%). Increases of a similar magnitude were observed for the average maximum and trough steady-state concentrations. Increasing the FBM dose from 1,200 to 2,400 mg/day also resulted in a proportional increase in the value of the aforementioned parameters. The apparent total-body clearance of VPA decreased from 0.175 mL/min/kg at baseline to 0.138 (-21%) and 0.115 mL/min/kg (-34%) at respective doses of 1,200 and 2,400 mg/day of FBM.

FBM did not influence the protein binding of VPA. Thus, the data suggest that the decrease in total-body clearance can be attributed to a decrease in metabolic clearance of VPA through the inhibition of β-oxidation (62).

Carbamazepine

A decrease in the steady-state plasma concentration of CBZ, ranging between 20% and 25%, has been observed in a number of clinical trials after introduction of FBM. However, in several of the trials CBZ and PHT were coadministered, and a possible role for PHT cannot be excluded. To elucidate the mechanism of the interaction, the pharmacokinetics of CBZ in nine patients with epilepsy were determined during CBZ monotherapy (≥800 mg/day) and, after coadministration of FBM, up to a maximum daily dose of 3,000 mg (62).

Subsequent to coadministration of FBM, the apparent total-body clearance increased from a mean (± SD) of 229.4 ± 68.7 to 324.3 ± 109.2 mL/hr/kg, a mean increase of 41%. Correspondingly, CBZ plasma concentration decreased from 7.46 ± 1.65 µg/mL to 5.14 ± 1.14 µg/mL (-31%). In contrast, the mean plasma concentration of CBZ 10,11-epoxide increased from 0.99 ± 0.26 µg/mL to 1.56 ± 0.42 µg/mL (57%). No significant change (7%) in CBZ diol concentration was observed.

The increase in steady-state CBZ 10,11-epoxide concentration can be explained either by induction of CBZ metabolism to the epoxide or by inhibition of epoxide hydrolysis to the diol. The relative contribution of each mechanism can be assessed by evaluating the metabolite-to-parent ratio. The epoxide-to-CBZ ratio increased by 138%. Most of this increase was due to an increase in the formation clearance of CBZ 10,11-epoxide.

The plasma protein binding of CBZ, CBZ 10,11-epoxide, and CBZ diol was unchanged (63) during coadministration with FBM at a daily dose of 3,000 mg, thus excluding a protein binding interaction.

Effect of Other Antiepileptic Drugs on Felbamate

Phenytoin

The consequence of a controlled discontinuation of PHT in four patients treated with FBM, PHT, and CBZ was an increase in FBM plasma concentrations. The corresponding mean decrease in the apparent total-body clearance of FBM was 21% (64). This observation was confirmed in a study of patients with epilepsy who were coadministered PHT and FBM (60). In this study, PHT (200 to 500 mg/day) caused an approximate doubling of the apparent total-body clearance of FBM (53 to 61 mL/hr/kg). Interestingly, in spite of the increase in clearance, the pharmacokinetics of FBM were still linear over the dose range 400 to 1,200 mg administered three times daily.

Carbamazepine

Patients who had successfully completed a gradual decrease in PHT dose experienced further increases in FBM plasma concentrations as their CBZ dose was decreased (64). A further mean reduction of 16.5% in apparent total-body clearance was reported. These data suggest that CBZ induced the clearance of FBM. In an open-label study with nine patients on CBZ monotherapy (≥800 mg/day) (62), the mean apparent clearance of FBM was approximately 40% greater than that observed in normal volunteers (26 mL/hr/kg). The mean half-life (14.6 hours) in patients coadministered CBZ was shorter (54) than in normal volunteers (20 hours).

Valproic Acid

VPA appears to have minimal effects on FBM steady-state plasma concentrations. An assessment of the effect of VPA on the pharmacokinetics of FBM was obtained from an open-label study in which patients on VPA monotherapy (9.2 to 26.2 mg/kg/day) were coadministered FBM 1,200 or 2,400 mg/day in a randomized, crossover fashion (65). No dose-dependent changes in clearance were observed. FBM clearance values after multiple-dose treatment at 1,200 or 2,400 mg/day were 25.9 and 27.6 mL/hr/kg, respectively, and terminal elimination half-life values were 22.2 and 21.7 hours, respectively. These values were the same as those reported in normal volunteers. AUC and trough plasma concentration increased linearly when the dose of FBM increased from 1,200 to 2,400 mg/day.

Gabapentin

Gabapentin has been reported to reduce the clearance of FBM and increase its serum concentration. The reported clearance of FBM decreased from 0.67 to 0.42 mL/kg/day-with an accompanying increase in half-life to 35 hours (146% of baseline) (66).

Other Pharmacokinetic Interactions

No clinically relevant pharmacokinetic interactions were noted between FBM and lamotrigine, clonazepam, vigabatrin, or the active monohydroxv metabolite of oxcarbazepine. Information on the mechanisms underlying FBM's drug-drug interaction profile permits predictions to

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be made concerning the likelihood of interactions with other compounds.

 

FIGURE 27.4. Effects of other drugs.

A summary of the effects of other drugs on FBM trough concentrations is depicted in Figure 27.4.

CLINICAL USE

FBM was the first of a new generation of AEDs to be approved in the United States after a gap of nearly 15 years. The experience with FBM has provided many lessons. The Central Nervous System Advisory Committee of the U.S. Food and Drug Administration (FDA) recommended FBM for approval in December 1992. FBM was marketed in the United States on July 30, 1993 for monotherapy and adjunctive treatment of partial seizures with or without generalization, in adults, and as adjunctive therapy for partial and generalized seizures associated with Lennox-Gastaut syndrome, in children. The clinical development program used novel study designs (67). These included the relatively acute administration of FBM after withdrawal from other AEDs in patients undergoing presurgical evaluations, and trials allowing FBM monotherapy. Before its launch, approximately 4,000 patients were exposed with FBM, with >900 receiving the drug for ≥6 months, and >500 treated for at least 1 year (6,68,69).

Efficacy

Localization-Related Epilepsies

Five studies evaluated the effect of FBM in patients with localization-related epilepsy (6); three studies used double-blind, placebo-controlled, add-on designs. Theodore et al. (70) used a three-period crossover study of FBM designed to estimate the importance of carryover effects, in 28 patients at a single center who had at least two complex partial seizures a week while taking CBZ (Figure 27.5). The decreases in seizure frequency compared with placebo—14%overall, 27% for partial seizures, and 12% for generalized tonic-clonic seizures—were not significant. FBM reduced CBZ levels by 24%. The maximum dose of FBM, 50 mg/kg, or 3,000 mg/day, was well tolerated. Mean FBM levels were 39 ± 11.5 mg/L. The only adverse effects occurring significantly more frequently with FBM than with placebo were nausea, diplopia, and blurred vision.

 

FIGURE 27.5. Percentage reduction of seizures in patients treated with felbamate compared with placebo in three doubleblind, add-on trials of complex partial seizures (CPS), secondarily generalized tonic-clonic seizures, (GTCS), and atonic seizures. Numbers in parentheses are reference numbers.

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Leppik et al. (71) reported a two-center study of FBM in 56 patients taking PHT and CBZ. Seizure frequency was 4.2% lower with FBM than during baseline and 23.4% lower than with placebo. The mean FBM dose was 2300 mg/day, and the mean plasma FBM level 32.5 mg/L. Although an unblinded monitor adjusted doses during the study to keep PHT and CBZ levels within each patient's baseline range, CBZ levels were 19% lower. Headache, dizziness, blurred vision, ataxia, nausea, and vomiting were reported more frequently when patients were taking FBM than when they were taking placebo.

In a multicenter study of 64 patients (72) who were being monitored for possible epilepsy surgery, the time to fourth seizure was significantly longer with 3,600 mg/day FBM (mean plasma FBM level, 65.1 mg/L) than with placebo. Forty-six percent of patients on FBM, compared with 88% on placebo, reached the fourth seizure end point (Figure 27.5). Patient were maintained on at least one other drug during the study. Headache, insomnia, and gastrointestinal disturbances were more common with FBM.

Two studies using an identical design compared FBM 3,600 mg/day with VPA 15 mg/kg/day (mean daily doses, 1,082 and 1,225 mg, respectively). The low doses of VPA were intended to protect patients from dangerous seizure exacerbation, but be less effective than FBM, in an attempt to test monotherapy efficacy versus an “active control” (73). Sachdeo et al. (74) randomized 44 patients (mean plasma FBM levels, 78.4 mg/L) and Faught et al. (75) randomized 111 patients (mean plasma FBM levels, 65 ± 23 mg/L) who had uncontrolled partial seizures during a 56-day baseline period, with other AEDs discontinued. During the 112-day trials, patients on VPA were significantly more likely to drop out owing to increased seizure frequency or severity: 40% on FBM versus 78% on VPA in one (75), and 18% versus 91% in the other study (74) (Figure 27.6). Combined data from the two studies showed that 29% of the patients on FBM, compared with 11% on low-dose VPA, had a reduction in seizure frequency of 50% or greater (76).

 

FIGURE 27.6. Percentage of patients taking felbamate compared with placebo (73) or low doses of valproic acid (75,76) who reached a defined seizure frequency or severity end point. Patients on felbamate were more likely to complete the trial in each study. Numbers in parentheses are reference numbers.

Generalized Epilepsies

In one study (77), FBM (45 mg/kg or 3,600 mg/day) or placebo was administered for 70 days to 73 patients with Lennox-Gastaut syndrome, aged 4 to 36 years (mean, 13 years), who had a history of multiple seizure types (including at least 90 atonic or atypical absence seizures a month), were taking up to two AEDs, had a slow spike-and-wave pattern on the electroencephalogram (EEG), and had no evidence of progressive neurologic disease. The main outcome variable was seizure count, as recorded in 4-hour periods of video-EEG monitoring, which did not have a statistically significant effect. When seizure counts by the parents or guardians were compared, FBM reduced seizure frequency by 19% compared with baseline, whereas the reduction was 7% for placebo (p = .01). Atonic seizure frequency was reduced by 34% with FBM and by 9% with placebo (p = .002). The effect of FBM on atonic seizures appeared to be greater at a dose of 45 mg/kg/day (mean plasma FBM level, 43.8 mg/L) than at a dose of 15 mg/kg/day. Subsequent data analysis (78, 79, 80, 81) showed that 47% of patients had a reduction of 57% in atonic seizures. Of interest is the seeming correlation of efficacy with rising serum levels. Doses of 5,000 to 6,000 mg/day have been administered to adults and those greater than 60 to 90 mg/kg/day to children (78, 79, 80). Anorexia, vomiting, and sleepiness occurred more frequently with FBM than with placebo. Global evaluation scores on a seven-point scale, from ratings by parents or guardians, were significantly better with FBM than with placebo. A subsequent follow-on, open-label study demonstrated that after 12 months, improvement on FBM was sustained. Also, a ≥50% reduction in seizure frequency was observed in 62% of children who initially received placebo after FBM was added (81).

Reports in small patient groups suggest that FBM may be effective in absence (82) or juvenile myoclonic epilepsy (83) and infantile spasms (71) when other drugs have failed.

Toxicity

Clinical Trials

More than 1,600 subjects were enrolled in the FBM clinical trials (7). The average age of the patients studied was 30 years. The patients in the Lennox-Gastaut trials included children as young as 4 years of age (77,81).

In all the clinical trials, the overall mean duration of exposure to FBM was 372 days. A total of 910 patients received FBM as monotherapy. For patients receiving adjunctive therapy, the mean duration of treatment was 347 days. The mean duration of treatment was 286 days for the monotherapy group. For patients receiving both adjunctive

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therapy and monotherapy, the mean duration was 383 days. In the children who received FBM, the overall duration of exposure was 293 days. Seventy-six children received FBM as monotherapy for a mean of 268 days, and 306 received FBM as adjunctive therapy for a mean of 274 days. Children who received both adjunctive therapy and monotherapy were treated for a mean of 383 days (7).

Most clinical trials with FBM followed the current recommended dosage schedule. Children were started on 15 mg/kg/day, increased at 7-day intervals to 30 mg/kg/day, and finally 45 mg/kg/day, or 3,000 mg. Adults began at 1,200 mg/day in three or four divided doses, and were increased every 7 days to 2,400 mg, and finally to 3,600 mg a day. The FBM dosage could be increased more quickly (6 to 7 days) when it was used as monotherapy (74,75). The presurgical study rapidly titrated FBM successfully up to 3,600 mg over a 3-day period without significant side effects (72).

Reports of overdosage with FBM have been limited. There is one report of attempted suicide by a subject who ingested 12,000 mg of FBM in a 12-hour period. Mild gastric distress and resting heart rate of 100 beats/min were the only problems reported. Overall, there have been no serious adverse effects from overdosages of FBM. If overdosages do occur, general supportive measures are recommended. It is not known if FBM is dialyzable (7).

On the basis of more recent clinical experience, it appears that a slower increase of FBM dosage, similar to that recommended outside the United States, may alleviate the most common adverse effects. In clinical practice, many of the adverse effects seem to be associated with rapid increases of the drug to target doses, and the adverse effects are exacerbated when FBM is used as adjunctive therapy (69).

Experimental Toxicology

Acute FBM toxicity evaluated in the mouse and rat indicated central nervous system stimulation, including hypoactivity, decreased muscle tone, ptosis, ataxia, loss of righting reflex, prostration, tremor, labored breathing, and death. The oral median lethal dose (LD50) for rats and mice was >5,000 mg/kg. The intraperitoneal LD50 ranged from 475 to 2,233 mg/kg in the mouse and from 1,625 to 4,500 mg/kg in the rat (7).

In subchronic toxicity studies, body weight or body weight gain was significantly reduced in a dose-dependent manner in animals receiving FBM. Food consumption also was reduced. In both the 13-week and 1-year toxicity studies in dogs (up to 1,000 mg/kg and at 300 mg/kg, respectively), limb rigidity, seizures, ataxia, emesis, and salivation were noted; these symptoms typically were observed within the first 2 weeks of dosing. There were no consistent drug-related changes in clinical chemistry or hematologic parameters in any of the studies. Morphologic changes in the liver indicative of enzyme induction (i.e., increase in cytoplasmic volume, cytoplasmic vesiculation, and hepatic cell parenchyma) and the presence of intracytoplasmic myelin figures were observed in the high-dose FBM groups in both the subchronic and chronic toxicity study in the rat and the subchronic toxicity study in mice, but not in either dog study.

Carcinogenicity studies revealed that the oral administration of FBM did not increase the incidence of malignant or nonmalignant neoplasms or affect the longevity of either mice or rats. FBM showed no in vitro mutagenic effects. In addition, FBM in doses up to 2,000 mg/kg did not significantly increase the number of chromosomal aberrations per cell or the proportion of aberrant metaphases in rat bone marrow cells (7). In reproductive toxicity studies, FBM was nonteratogenic in the rat or rabbit because there were no visceral or skeletal variations or malformations observed in fetuses. In the rat, fetal exposure to drug and metabolites readily occurred because unrestricted placental transfer of [14C] FBM was apparent from the maternal-fetal blood flow 14C ratio.

Adverse Effects

During premarketing studies, the most common adverse reactions in adults receiving FBM monotherapy were anorexia, vomiting, insomnia, nausea, and headache. Similar symptoms were seen when FBM was used as adjunctive therapy, along with dizziness and somnolence. Adverse effects (5% incidence) were much higher when FBM was used as adjunctive therapy (G) (Table 27.2). Nausea, anorexia, and dizziness were reported in more than 5% of adult patients who received FBM as adjunctive therapy. Nausea was the only adverse effect that had a probable or definite relationship in more than 11% of adults on adjunctive therapy with FBM. The most common reasons for stopping FBM during adjunctive therapy were nausea, vomiting, anorexia, and insomnia. Most subjects did not require changes in FBM dosage. Almost all of the adverse effects resolved during the course of the studies, and were most likely the result of interactions between FBM and the standard AEDs. Whereas FBM interacts with CBZ by reducing the average plasma CBZ concentration by approximately 20%, there was an increase in the CBZ epoxide concentration of approximately 50%, and it is likely that many of the adverse effects were associated with the CBZ epoxide levels. FBM can increase PHT levels by approximately 20%. Thus, when FBM was introduced, PHT levels rose if the appropriate dosage reduction was not made, causing dose-related adverse effects. FBM also increased both the free and total plasma VPA levels. Because of the interactions of FBM, appropriate reductions in the doses of CBZ, PHT, and VPA may avoid many of the adverse effects.

In FBM monotherapy trials, nausea was the only problem that had a probable or definite relationship in more than 10% of adults on FBM monotherapy. Gastrointestinal complaints were the most common adverse effects and

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included nausea followed by anorexia, vomiting and dyspepsia, abdominal pain, diarrhea, and constipation. Neurologic symptoms reported included headache, the most common problem, dizziness, somnolence, and tremor. General physical complaints included fatigue and weight loss as the most common, followed by reports of injury and influenza-like symptoms. Insomnia was by far the most common psychological adverse effect, followed by nervousness and depression. There also were reports of diplopia and abnormal vision, as well as upper respiratory tract infections such as pharyngitis. Rash was uncommon, but rarely reported were leukopenia, thrombocytopenia, agranulocytosis, and Stevens-Johnson syndrome, usually when FBM was taken with other drugs (67,85).

The initial long-term safety data on FBM use in adults indicated that the most commonly occurring adverse effects were similar to those seen in earlier studies. There was no increase in the number of adverse effects reported in patients treated for 6 months or longer.

The issue of anorexia and weight loss was addressed in patients receiving FBM monotherapy for partial seizures (75). The reported incidence of weight loss and anorexia secondary to FBM ranges from 2% to 10% (7). The patients had a mean weight loss of 3 pounds from the baseline to the last trial visit, but the weight decrease was considered an adverse effect in only two of the patients.

The overall dropout rate from the clinical trials because of adverse effects or intercurrent illness in adult patients receiving FBM was 12%. The problems necessitating FBM discontinuation were gastrointestinal, 4.3%; psychological, 2.2%; whole-body, 1.7%; neurological, 1.5%; and dermatologic, 1.5% (7). More recently, seemingly rare urolithiasis during normal therapy and massive crystalluria and acute renal failure with FBM overdose have been reported (86,87).

Children

The adverse effects of FBM in children were much more common with adjunctive therapy than with monotherapy (7) (Table 27.2). A variety of symptoms occurred with FBM use as adjunctive therapy; anorexia was the most common gastrointestinal symptom, followed by vomiting, diarrhea, nausea, abdominal pain, and constipation. Similar symptoms were reported in patients receiving FBM monotherapy. Neurologic symptoms consisted of headache, somnolence, and dizziness. Adverse effects were far fewer in the FBM monotherapy group. Insomnia and nervousness were the most frequent psychological complaints. A few patients reported rash.

In children, only somnolence and anorexia (both 5.8%) and insomnia (5.5%) were considered probably or definitely related to FBM use (7). These adverse effects were reported in patients receiving FBM as adjunctive therapy. Less than 1% of patients receiving FBM adjunctive therapy had severe adverse effects. FBM was infrequently discontinued for the following reasons: gastrointestinal, neurologic, dermatologic, psychological, or whole-body complaints. The only specific problem in children that required withdrawal of FBM was rash.

The long-term adverse effects of FBM use in children were somnolence, anorexia, vomiting, and insomnia. The incidence of weight loss as an adverse effect was 2% in children receiving FBM as adjunctive therapy and 3% in children receiving FBM as monotherapy. The weight reduction was 3% to 5% of the patient's pretreatment body weight and was approximately 0.6 to 4 pounds. The weight loss appears to reach a plateau as FBM therapy is continued. Although weight loss usually is seen as a beneficial side effect, some multihandicapped children with feeding or weight gain difficulties have been removed from FBM because of the severity of this associated symptom.

Overall, the dropout rate from the clinical trials because of adverse effects in pediatric patients was approximately 10%, and the most common reasons for discontinuation of FBM were gastrointestinal and neurologic complaints.

CLINICAL LABORATORY VALUES IN ADULTS AND CHILDREN

The clinical laboratory testing done in the clinical trials of FBM in both adults and children indicated that monitoring of clinical laboratory values was not necessary for the safe use of FBM. Monitoring concurrent AED and FBM levels may be helpful, along with careful clinical assessment, to help manage adverse effects. The subsequent identification of idiosyncratic reactions has put a new light on this recommendation (69).

Several articles have discussed the relative risks of FBM-associated aplastic anemia or hepatic failure and its subsequent use in patients (69,90,91). The following sections present the hypothetical mechanism through which FBM may produce toxicity, an estimate of risks involved for patients, and recommendation for clinical use.

Hypothesis

Research efforts attempting to understand the unexpected occurrence of aplastic anemia and liver toxicity after use of FBM have focused on its metabolism. It has been hypothesized that FBM toxicity results from FBM bioactivation to a highly reactive α,β-unsaturated aldehyde, 2-phenylpropenal, whose chemical structure and reactivity are similar to known chemical alkylators such as the cyclophosphamide metabolite, acrolein, and lipid peroxidation products, such as 4-hydroxynonenal. These efforts strongly support the hypothesis that 2-phenylpropenal may be the reactive metabolite mediating FBM toxicity (93, 94, 95, 96, 97, 98, 99, 100). Thompson et al. (94) propose that in most patients undergoing FBM therapy, 2-phenylpropenal probably is detoxified by glutathione in the

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liver and undergoes further processing in the kidneys to the corresponding mercapturates (94). Excretion of mercapturates have been observed in the urine of all patients being treated with FBM (94,95). It is likely that a small number of patients receiving FBM therapy may become glutathione depleted, resulting in a compromised ability to detoxify 2-phenylpropanel, thereby increasing the risk for FBM toxicity.

Given the hypothesis that glutathione-depleted patients are at risk for FBM toxicity, a patient metabolite urinalysis assay was developed to monitor patients taking FBM for their epilepsy (95). The urine metabolite assay is based on our understanding of FBM metabolism. FBM is metabolized to an intermediate aldehyde carbamate metabolite that has two ultimate fates: oxidation to the corresponding acid carbamate, or β-elimination to form 2-phenylpropenal. The formation of 2-phenylpropenal can be measured by quantification of the corresponding mercapturates in patient urine. Given that the patient population metabolizes FBM in a regular manner, the ratio of acid carbamate to mercapturates in patient urine should produce a constant number. In fact, the results of the first 31 patients tested produced a constant ratio of 2.2 (95). Patients who then become glutathione depleted should excrete relatively fewer mercapturates, resulting in an increase in the ratio of acid carbamate to mercapturates.

The results from the first 31 patients were encouraging and supported the metabolite urine assay as a means to monitor patients at potential risk for FBM toxicity. More recently, Dieckhaus et al. (101) reported the use of single-time-point urine collection over 24-hour urine collection, demonstrating trends in the ratio of acid carbamate to mercapturates in 1,000 patients naive to FBM therapy. Evaluation of the first 1,000 patients revealed an outlier whose ratio was greater than 20 SD from the norm who presented with neutropenia. Taken together, the data suggest that FBM patient urine metabolite monitoring may be a useful means of predicting patients who may be at risk for FBM toxicity. Further work is underway to explore and validate this hypothesis.

Idiosyncratic Reactions

A single case of aplastic anemia associated with combination CBZ and FBM therapy was reported in February 1994. By mid-1994, a trickle of similar reports began to appear. On August 1, 1994, Carter Wallace, supported by the FDA, sent letters to nearly 250,000 physicians alerting them to this new risk associated with FBM treatment, and urgently recommended discontinuation of FBM in most patients, but in September 1994 the FDA Advisory Committee voted to allow FBM to remain on the market. By the autumn of 1994, cases of hepatic failure, including four deaths, also had been associated with FBM treatment (69).

Although physicians and patients were warned not to discontinue FBM abruptly, some individuals stopped taking it immediately and had serious exacerbations of their seizure disorder. Several incidences of status epilepticus resulted (69,88). Some patients chose to continue treatment with FBM because they had experienced a remarkable improvement in seizure control and often in their quality of life as well (68). FBM continues to be used in approximately 10,000 to 15,000 patients previously controlled on FBM or in those with refractory partial or generalized epilepsy, but it now is used as a third- or fourth-line AED.

Aplastic Anemia

Currently, approximately 36 cases of FBM-associated aplastic anemia have been reported. By 1999, 33 cases in the United States and a few additional cases internationally had been reported (91). Only one has been identified since 1999. The demographics of the patients reported to have aplastic anemia reveal that they were predominately female (67%), white (94%), adults (mean age, 42.5 years), receiving a mean FBM dose of 3,129 mg/day (range, 800 to 5400 mg/day), and the mean time to onset was 173 days (range, 23 to 339 days). The incidence of aplastic anemia attributed to FBM using all 33 reported cases was estimated at 300 per million patients treated.

Evaluation of the demographic characteristics and patient history revealed several features that appeared regularly and may profile the patient who is at risk. Aside from being predominantly female, 17 of the 33 patients (52%) had a prior history of anticonvulsant allergy or toxicity (especially rash), 14 had a history of prior cytopenia (42%), and 11 (33%) had evidence of immune disease (Table 27.3). Whether those patients with prior serious anticonvulsant allergy/toxicity, immune disorder, and prior history of cytopenia are truly at risk remains to be determined. It also is important to consider that four patients in whom aplastic anemia developed had none of the aforementioned risk factors (92).

On review of the first 31 reports received by the Slone Epidemiology Unit of Boston University using the International Agranulocytosis and Aplastic Anemia Study guidelines,

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only 23 cases (74%) met the criteria for aplastic anemia (92). FBM was judged to be the only plausible cause (unlikely confounding factors) in 3 cases (13%) and confounded but a likely possible cause in 11 cases; there was at least one other plausible cause in another 9 patients. In the worst-case scenario (using all 23 cases defined as aplastic anemia), the estimated incidence is 109 cases per million. In the best-case scenario (i.e., the 3 cases with unlikely confounding factors), the incidence is as low as 27 per million patients treated. This is opposed to an incidence of 2 to 2.5 per million in the general population. The overall risk for development of aplastic anemia when initiating FBM has been estimated at 1/3,000 to 1/5,000 cases per year, but one would have expected several more cases to have been identified subsequently (90,91). The risk of aplastic anemia with FBM may be 20 times that with CBZ therapy (91).

TABLE 27.3. PROFILE OF THE PATIENT AT RISK FOR FELBAMATE-RELATED APLASTIC ANEMIA

Potential Risk Factor

Percentage of Patients (n = 33)a

Age >17 yr

97

Female sex

67

Concomitant medications

79

Concomitant anticonvulsants

55

History significant for anticonvulsant toxicity/allergy

52

History of prior cytopenia

42

History of immune disease

33

a Analysis includes all reported cases to date, regardless of definitive diagnosis of aplastic anemia.

A review of the demographic profile of patients with reported aplastic anemia suggests that there may be a patient profile to aid in evaluating the individual patient at risk. Available data suggest the “at-risk” patient appears to be a middle-aged woman with a clinical history of a previous cytopenia (particularly thrombocytopenia), evidence of an underlying immunologic disorder (lupus, arthritis, or elevated antinuclear antibodies), and a significant history of prior anticonvulsant allergy. There has been only one pediatric patient diagnosed with aplastic anemia. However, this 13-year-old postpubertal girl with a history of mental retardation had a pre-FBM exposure diagnosis of systemic lupus erythematosus (91).

Hepatotoxicity

Eighteen cases of hepatic failure were reported in patients receiving FBM; evaluation indicated that 78% were female, 50% were 17 years of age or older, and the mean time to presentation was 217 days (range, 25 to 939 days). Of the patients, 16 were receiving other anticonvulsants. Using all reported cases of hepatic failure, the estimated incidence is 164 per million patients treated.

A further review suggested that only seven had a likely connection with FBM. Other cases were complicated by status epilepticus, viral hepatitis, shock liver, and paracetamol (acetaminophen) toxicity. The age range for those with a likely relationship to FBM was 5 to 56 years, and six of the seven patients were female. Using a numerator of 7, the incidence of hepatic failure would be approximately 64 per million patients treated. This incidence overlaps with the overall occurrence of VPA-associated hepatic failure, but for FBM there seems to be no clear age prediction, as seen with VPA (91).

Recommendations

A practice advisory was issued concerning “the use of FBM in the treatment of patients with intractable epilepsy” by the American Academy of Neurology, Subcommittee on Quality Standards in 1999 (91). They found sufficient evidence to recommend the use of FBM in several partial and generalized epilepsy syndromes, and balanced the severity of these conditions against the risk of life-threatening serious adverse effects (Table 27.4).

The clinical profile of patients at greatest risk and the proposed metabolic hypothesis presented previously may allow further delineation of patients at greatest risk.

FBM should be reserved for treatment of those adults and children with severe epilepsy refractory to other therapies, especially for patients with Lennox-Gastaut syndrome. Before beginning FBM treatment, a careful history concerning past indications of hematologic and hepatic toxicity, and of autoimmune disease, should be sought. Baseline routine hematologic and liver function tests should be performed, and patients and their families must be carefully informed of the potential risks; in the United States, written consent is recommended. Dose escalations should be made slowly, and dosages of comedication must be corrected

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for known interactions where possible. A move to monotherapy should be a goal before FBM is added, using a clear, well-thought-out plan. There must be frequent and thorough clinical monitoring visits, and patients must be educated about symptoms that might herald either hematologic or hepatic toxicity. Urinary monitoring for FBM metabolites, as described earlier, may offer additional evidence of degree of risk, but is not established as a standard. If the desired clinical effect is not achieved at a reasonable dose in a timely manner, FBM should be discontinued.

TABLE 27.4. THE USE OF FELBAMATE IN THE TREATMENT OF PATIENTS WITH INTRACTABLE EPILEPSY

1.    Patients for whom risk/benefit ratio supports use because there is class I evidence for benefit

1.    Patients with Lennox-Gastaut syndrome older than age 4 yr unresponsive to primary AEDs

2.    Intractable partial seizures in patients older than 18 yr of age who have failed standard AEDs at therapeutic levels (monotherapy: data indicate a better risk/benefit ratio for felbamate used as monotherapy)

3.    Patients on felbamate >18 mo

2.    Patients for whom the current risk/benefit assessment does not support the use of felbamate

1.    New-onset epilepsy in adults or children

2.    Patients who have experienced significant prior hematologic adverse events

3.    Patients in whom follow-up and compliance will not allow careful monitoring

4.    Patients unable to discuss risks/benefits (i.e., with mental retardation, developmental disability) and for whom no parent or legal guardian is available to provide consent.

3.    Patients in whom risk/benefit ratio is unclear and based on case reports and expert opinion (class III) only, but under certain circumstances depending on the nature and severity of the patient's seizure disorder, felbamate use may be appropriate

1.    Children with intractable partial epilepsy

2.    Other generalized epilepsies unresponsive to primary agents

3.    Patients who experience unacceptable sedative or cognitive side effects with traditional AEDs

4.    Lennox-Gastaut syndrome in patients younger than 4 yr of age unresponsive to other AED

AED, antiepileptic drug.

From Kaufman DW, Kelly JP, Anderson T, et al. Evaluation of the case reports of aplastic anemia among patients treated with felbamate. Epilepsia 1997;38:1265-1269, with permission.

CONCLUSION

FBM was introduced in the United States in 1993 as the first new AED after nearly 15 years. Efficacy was established for both partial and generalized epilepsy in adjunctive and monotherapy studies, after a number of preclinical studies suggesting a broad spectrum of activity. Its initial clinical toxicity profile suggested an acceptable risk as patients brightened and lost weight, rather than the contrary. The subsequent identification of life-threatening aplastic anemia and hepatotoxicity have relegated FBM to the status of a less preferred AED, but one that should be considered in the treatment of refractory epilepsy.

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