VA Class:CN400

AHFS Class:

• Anticonvulsants, Miscellaneous 28:12.92

Generic Name(s):

• Felbamate

Chemical Name:

• 2-Phenyltrimethylene ester carbamic acid

Molecular Formula:

• C₁₁H₁₄N₂O₄

Felbamate, a dicarbamate, is an anticonvulsant.1,3,4,5,20

In July 1993, felbamate (Felbatol^®) originally was approved by the FDA for use as monotherapy or in combination with other anticonvulsant agents in the management of partial seizures with or without secondary generalization in adults.1,8,12,13,14,19,20,21,22,25,40 Felbamate also was approved by FDA at that time for use in combination with other anticonvulsant agents in the management of partial and generalized seizures associated with Lennox-Gastaut syndrome in children1,15,16,17,20,21,25,40 and has been designated an orphan drug by FDA for the treatment of this latter syndrome.2 However, because felbamate has since been associated with marked increases in the incidences of aplastic anemia and acute hepatic failure, the drug is currently reserved for use only in patients who have not responded adequately to alternative safer treatments and whose seizure disorder is so severe that the risks of the drug are considered acceptable in light of the potential benefits.26,28,29,31,40,258 Decisions about the potential benefits and risks of felbamate therapy generally should be made in consultation with appropriate hematologic and hepatic disease experts.19,27,40 (See Cautions.)

Felbamate is currently available in the US for patients with severe, refractory seizure disorders in whom the benefits of the drug are considered to outweigh the potential risks of aplastic anemia and hepatic failure.19,21,22,24,26,28,29,33,40 However, clinicians should prescribe felbamate only if therapy with the drug is absolutely necessary.21 Therapy with felbamate should be initiated or continued only after the risks associated with the drug have been discussed completely with the patient, parent, or guardian, and a written acknowledgment form has been obtained and signed by the patient and physician.32,40 All cases of aplastic anemia or acute hepatic failure associated with felbamate therapy should be reported promptly to the manufacturer or to FDA MedWatch by phone (800-FDA-1088) or website ([Web]).28,32,34,40,41,42

Although the comparative efficacy of therapeutically effective dosages remains to be established, the anticonvulsant potential of felbamate in patients with partial seizures with or without secondary generalization has been established in studies comparing therapeutic dosages of felbamate with relatively low dosages of valproic acid.1,8,11 In 2 such studies, adult patients with partial seizures were randomly assigned to receive either felbamate up to 3.6 g daily administered in 4 divided doses or valproic acid 15 mg/kg daily during a 112-day treatment period.1,8,11 Both studies were designed only to demonstrate the anticonvulsant activity of felbamate monotherapy using low-dosage valproate as a control; this study design, described as a low-dose active-control trial, is intended to avoid the interpretational difficulties of no-difference (i.e., equivalent) therapeutic outcomes in studies of investigational anticonvulsant agents and therefore is not intended to determine comparative efficacy.8,9,10,11,18,19 The primary variable used to measure anticonvulsant activity was the number of patients in each group who met at least one of the following escape criteria and consequently exited the study: (1) a twofold increase in average monthly seizure frequency, (2) a twofold increase in the highest 2-day seizure frequency, (3) a single generalized tonic-clonic seizure if none occurred during the baseline period, or (4) a prolongation of generalized seizure duration (serial seizures or status epilepticus) deemed by the investigator to require intervention.1,8,11,18 In these studies, 14-40% of patients receiving felbamate met escape criteria and exited the study compared with 78-90% of patients receiving low-dosage valproic acid, indicating that felbamate alone has anticonvulsant activity in patients with partial seizures;8,11 however, because of the study design, no conclusions regarding comparative efficacy with valproic acid can be made .9,10,11,18

Felbamate also may potentiate the anticonvulsant activity of other agents in the management of refractory partial seizures.1,12 In a double-blind, placebo-controlled crossover trial, patients with refractory partial seizures who received felbamate administered concomitantly with phenytoin and carbamazepine had fewer seizures during each treatment sequence than patients who received placebo with phenytoin and carbamazepine.1,12 However, in a 3-period, crossover study of patients with complex partial seizures receiving carbamazepine in combination with either felbamate (usually 3 g daily) or placebo, felbamate-induced reductions in plasma concentrations of carbamazepine were believed to have contributed to the lack of effect of the drug on seizure frequency.13 Among patients who underwent reduction or discontinuance of a standard regimen of anticonvulsant therapy during evaluation for surgery of an intractable seizure disorder, those who subsequently received concomitant felbamate had greater time to onset of fourth seizure than patients who received placebo.1,14,18

In children with Lennox-Gastaut syndrome, maximum tolerated dosage of felbamate (up to 45 mg/kg [not exceeding 3.6 g] daily) has reduced the frequency of atonic seizures, generalized tonic-clonic seizures, and total seizures when added to the patient's standard regimen of anticonvulsant therapy.1,15,16,17 Improvements in quality-of-life parameters (increased alertness and verbal responsiveness) also have been reported by parents or guardians in such children.1,15,17

The efficacy of monotherapy or combination therapy with felbamate for the management of partial seizures and Lennox-Gastaut syndrome reportedly is not influenced by patient gender.1

Administration

Felbamate is administered orally (as tablets or oral suspension).40,41,42 The manufacturer states that both the commercially available tablet and oral suspension have been shown to be bioequivalent to the capsule formulation used in clinical trials; the pharmacokinetic profiles of the tablet and oral suspension are similar.40 Food does not appear to affect absorption of felbamate tablets; the effect of food on absorption of the oral suspension has not been evaluated.40,41,42

Patients who are currently receiving or beginning therapy with felbamate and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.35,37,40 (See Cautions: Nervous System Effects and see Cautions: Precautions and Contraindications.)

Dosage

Dosage of felbamate must be carefully and slowly adjusted according to individual requirements and response.1 Felbamate should be withdrawn slowly because abrupt discontinuance of the drug may precipitate seizures.40 (See Cautions: Precautions and Contraindications.)

When felbamate is used as initial monotherapy, therapy should begin with a low dosage of the drug and slowly increased.40 When felbamate is added to an existing anticonvulsant regimen, the drug should be added gradually while dosage of the other anticonvulsant(s) is decreased to reduce the risk of adverse effects from drug interactions.40 When transferring patients from combination therapy to monotherapy with felbamate, dosage of felbamate should be increased gradually while dosages of other anticonvulsant agents should be decreased gradually and discontinued.40

The initial dosage of felbamate as monotherapy or adjunctive therapy (i.e., in combination with other anticonvulsants) for the management of partial seizures in adults and adolescents 14 years of age or older is 1.2 g daily administered in 3 or 4 divided doses.40 Subsequent dosage may be increased gradually based on clinical response; recommended titration increments and schedules are based on whether the patient is receiving felbamate as initial monotherapy or adjunctive therapy, or converting from combination therapy to felbamate monotherapy.40 The majority of patients in both monotherapy and adjunctive trials received a felbamate dosage of 3.6 g daily.40 More rapid titration of felbamate dosage than that currently suggested by the manufacturer occasionally has been employed.8,11,14

For patients with partial seizures receiving felbamate as initial monotherapy , the initial felbamate dosage may be increased by 600-mg daily increments at 2-week intervals to 2.4 g daily administered in 3 or 4 divided doses or until optimum clinical response is obtained.40 Clinicians are advised to titrate previously untreated patients under close medical supervision.40 If adequate seizure control has not been achieved and further increases in monotherapy dosage are considered clinically necessary, felbamate dosage may be titrated further to 3.6 g daily.19,40 Felbamate has not been evaluated systematically as initial monotherapy.40

For patients with partial seizures converting from combination therapy to felbamate monotherapy , the initial felbamate dosage may be increased by 1.2-g daily increments at weekly intervals up to 3.6 g daily administered in 3 or 4 divided doses.40 As felbamate replaces the existing anticonvulsant regimen, dosage(s) of the other anticonvulsant(s) should be gradually reduced (by 33% of the baseline dosage in the first week, then an additional 33% or less of the baseline dosage in the second week, and then as clinically indicated in the third week) and discontinued.40

For patients with partial seizures receiving felbamate as adjunctive therapy with other anticonvulsant agents (e.g., phenytoin, valproic acid, phenobarbital, carbamazepine), the initial felbamate dosage may be increased by 1.2-g daily increments at weekly intervals up to 3.6 g daily administered in 3 or 4 divided doses.40 Dosage(s) of the other anticonvulsant(s) must be reduced initially by at least 20%; further reductions in dosage(s) of concomitant anticonvulsant(s) may be necessary to avoid adverse effects caused by drug interactions.15,19,40

The usual initial dosage of felbamate as adjunctive therapy for the management of Lennox-Gastaut syndrome in children 2-14 years of age is 15 mg/kg daily administered in 3 or 4 divided doses.15,40 Dosage may be increased by 15 mg/kg daily at weekly intervals to 45 mg/kg daily administered in 3 or 4 divided doses.15,40 As felbamate is added to existing anticonvulsants (e.g., phenytoin, valproic acid, phenobarbital, carbamazepine), the dosage(s) of the other anticonvulsant(s) must be decreased initially by at least 20%;15,19,40 further reductions in dosage(s) of concomitant anticonvulsant(s) may be necessary to avoid adverse effects caused by drug interactions.19,40

Dosage in Renal and Hepatic Impairment

The manufacturer states that initial and maintenance dosages of felbamate should be reduced by 50% in patients with renal impairment.40 Adjunctive therapy with drugs that affect plasma felbamate concentrations, especially other anticonvulsants, may warrant further reductions in felbamate daily dosage in patients with renal impairment.40

Felbamate should not be used in patients with hepatic impairment.40

Dosage in Geriatric Patients

If felbamate is used in geriatric patients, the initial dosage usually should be at the low end of the dosage range.40 (See Cautions: Geriatric Precautions.)

Felbamate has been associated with marked increases in the incidences of aplastic anemia and acute hepatic failure.19,21,22,26,29,31,40 The drug should only be initiated or continued in the management of seizures in patients for whom, in the clinician's judgment, the seizure disorder is refractory to alternative safer therapy and is so severe that the benefits of felbamate therapy are believed to outweigh the possible risk of aplastic anemia26,31,40 or acute hepatic failure.28,29,40 (See Uses and see Cautions: Precautions and Contraindications.)

At least 21 cases (20 of which occurred in the US) of aplastic anemia were initially reported in association with felbamate therapy during the first several years of the drug's availability.19,26,27,31 The rate of aplastic anemia cases currently reported with the drug may be more than 100 times higher than the expected rate of 2-5 cases per million untreated individuals per year in the general population.21,22,26,31,40 While postmarketing surveillance usually captures only a fraction of incident cases, the syndrome is still relatively rare, and no cases were observed during premarketing testing in which more than 1600 patients received felbamate therapy.19,21,22 Clinical manifestations of aplastic anemia (e.g., bleeding, infection) may develop without premonitory clinical or laboratory signs, usually after several months of therapy (5-30 weeks); however, the injury to bone marrow stem cells that is thought to be responsible for anemia may occur much earlier.40

While current experience and data are too limited to estimate reliably the fatality rate associated with felbamate-induced aplastic anemia, the estimated case fatality rate for untreated individuals with aplastic anemia from any cause ranges from 20-30%.19,40 However, historical fatality rates as high as 70% have been reported for aplastic anemia, and the risk of death secondary to this anemia generally varies with severity and etiology.19,40 Risk factors for the development of aplastic anemia in patients receiving felbamate therapy have not been identified.22,26,31,40 Whether age (range for cases to date: 12-68 years old), gender, or race of the patient, duration of exposure to the drug, dosage, or concomitant use of other anticonvulsant agents or drugs affects the incidence of aplastic anemia in patients receiving felbamate remains to be established.26,31,40 Routine blood testing may allow for early detection of hematologic changes, but cannot be relied upon to avoid or reduce the risk of aplastic anemia.40 (See Cautions: Precautions and Contraindications.) Felbamate therapy should be discontinued if any evidence of bone marrow depression occurs.40 Patients may continue to be at risk of aplastic anemia for a variable, and unknown, duration following drug discontinuance.40

At least 10 cases (all from the US) of acute hepatic failure were initially reported in association with felbamate therapy during the first several years of the drug's availability; some cases resulted in death or liver transplantation.19,28,29 These cases were reported as part of the ongoing postmarketing surveillance program, and no cases of acute hepatic failure were observed during premarketing testing.28 The risk of acute hepatic failure resulting in death or liver transplantation currently has been reported at an estimated rate of 6 cases per 75,000 patient years of felbamate use in the US; however, the actual rate may be considerably higher.40 Severe hepatic dysfunction followed by hepatic failure has been reported as early as 3 weeks after initiation of felbamate; death or liver transplantation was required in about 67% of the reported cases, usually within 5 weeks of the onset of signs and symptoms of liver failure.40 Prodromal symptoms (e.g., anorexia, malaise, other GI symptoms) and/or dark urine may or may not precede the onset of jaundice.40

Whether preexisting hepatic impairment increases the risk of fulminant hepatic failure is unknown;28 however, all patients should be evaluated for evidence of hepatic impairment prior to initiation of felbamate therapy.27,28,40 Felbamate should not be initiated in patients with active liver disease, abnormal baseline serum transaminase concentrations, or a history of hepatic dysfunction.40 Other risk factors for the development of acute hepatic failure in patients receiving felbamate have not been identified.27,28,40 Whether age (range for cases to date: 5-78 years old), gender, or race of the patient, duration of exposure to the drug, dosage, or concomitant use of other anticonvulsant agents or drugs affects the incidence of acute hepatic failure in patients receiving felbamate remains to be established.19,27,28,40 Routine monitoring of serum transaminase concentrations (ALT and AST) has not been proven to prevent serious injury, but may allow early detection of drug-induced hepatic changes.40 (See Cautions: Precautions and Contraindications.) Felbamate should be discontinued if clinical manifestations suggestive of liver failure develop or AST/ALT concentrations increase to 2 or more times the upper limit of normal (ULN).40 Continued monitoring of hepatic function is recommended until liver abnormalities resolve.40 Reinitiation of therapy is not recommended in patients who develop evidence of hepatocellular injury and are withdrawn from felbamate for any reason.40

Other adverse effects of felbamate usually are mild to moderate in severity and self-limiting, infrequently requiring dosage adjustment.6,7,8,12,13,14,15 GI tract and nervous system effects are the most frequent adverse effects of felbamate1,7,8,11,12,13,14,15,20 and the adverse effects most frequently requiring discontinuance of the drug.1,11,14,15,20 In adults, the most frequent adverse effects of felbamate during monotherapy or adjunctive therapy are anorexia, nausea, vomiting, insomnia, and headache; dizziness and somnolence also are frequent during adjunctive therapy.1,11,12,14,20 In children, the most frequent adverse effects of the drug during adjunctive therapy are anorexia, vomiting, insomnia, headache, and somnolence.1,16 Discontinuance of felbamate because of adverse effects or intercurrent illness was required in about 12% of adults and 6% of children receiving felbamate in open-label and controlled clinical trials.1

The frequency of most adverse effects associated with felbamate appears to be lower during monotherapy than adjunctive therapy.1,7,8,11,20 Many adverse effects that occurred during clinical trials of felbamate adjunctive therapy (in dosages up to 3.6 g daily) may have resulted from drug interactions.1,8,11,12,20 Adverse effects that occurred during adjunctive therapy in clinical trials usually resolved following conversion to felbamate monotherapy or with dosage adjustment of the other concomitantly administered anticonvulsant agents.1,8,11,12 Because many of the clinical trials with felbamate involved specific patient populations and uses, including adjunctive therapy in which many of the adverse effects may have resulted from drug interactions, it is difficult to determine whether a causal relationship exists for many reported adverse effects, to compare adverse effect frequencies with other clinical reports, and/or to extrapolate the adverse effect experience from controlled clinical trials to usual clinical practice.1

Hematologic Effects

Use of felbamate has been associated with a marked increase in the incidence of aplastic anemia, which in some cases has resulted in death.19,22,26,27,31,40 (See introductory discussion in Cautions and Cautions: Precautions and Contraindications.)

Purpura1,15 occurred in about 13%1 and leukopenia1,15 in about 6% of children receiving felbamate as adjunctive therapy in controlled clinical trials.1 Lymphadenopathy,1 leukopenia,1 granulocytopenia,1 leukocytosis,1 and thrombocytopenia1,20 occurred in less than 1%1 and agranulocytosis,1,20 positive antinuclear factor test results,1 and qualitative platelet disorder1 occurred in less than 0.1% of adults and children receiving felbamate.1 Increased and decreased prothrombin time,27 anemia,27 hypochromic anemia,27 pancytopenia,27 and hemolytic uremic syndrome27 also have been reported in patients receiving felbamate.

Hepatic Effects

Use of felbamate has been associated with a marked increase in the incidence of acute hepatic failure, which in some cases has resulted in death or liver transplantation.19,27,28,29,40 (See introductory discussion in Cautions and Cautions: Precautions and Contraindications.)

Increased serum concentrations of ALT (SGPT)1,11 occurred in about 5% of adults receiving felbamate as monotherapy1 and about 4% receiving the drug as adjunctive therapy in controlled clinical trials.1,15 Increased serum concentrations of AST (SGOT)1,11,15 occurred in at least 1%,1 increased serum concentrations of LDH or alkaline phosphatase in less than 1%,1,15 and increased serum concentrations of γ-glutamyltransferase (GT, γ-glutamyltranspeptidase, GGTP) in less than 0.1% of patients receiving felbamate.1 Hepatitis,27 hyperammonemia,27 and jaundice27 also have been reported in patients receiving the drug.

GI Effects

Adverse GI effects were among the most frequent adverse effects reported in adults and children receiving felbamate in controlled clinical trials.1,8,11,12,13,14,15,20 In adults, adverse GI effects1,11,14 were the most common adverse effects resulting in discontinuance of the drug, which occurred in 4.3% of patients.1

Nausea1,8,11,12,13,14,20 was the most frequent adverse GI effect in adults, occurring in about 34% receiving felbamate as adjunctive therapy and requiring discontinuance in 1.4% of patients.1 Anorexia1,8,11,14,15,20 occurred in about 19% of adults and about 55% of children receiving felbamate as adjunctive therapy, and required discontinuance in 1.6% of adults;1 in one study in adults, anorexia was the only adverse effect that tended to persist when patients were switched from felbamate and adjunctive therapy to monotherapy.11 Vomiting1,8,11,12,13,14,15,20 was reported in about 17% of adults and about 39% of children receiving felbamate as adjunctive therapy, and in about 9% of adults receiving the drug as monotherapy.1 Dyspepsia1,8,11,14,20 occurred in about 12% of adults and about 7% of children receiving felbamate as adjunctive therapy, and in about 9% of adults receiving the drug as monotherapy.1 Constipation1,8,14,20 was reported in about 11% of adults and about 13% of children receiving felbamate as adjunctive therapy, and in about 7% of adults receiving the drug as monotherapy.1 Diarrhea1,8,11,20 occurred in about 5% of adults receiving felbamate as monotherapy or adjunctive therapy.1 Abdominal pain1,8,11 was reported in about 5% of adults,1 dry mouth in about 3% of adults,1 taste perversion1,8 in about 6% of adults,1 and nausea in about 7%1 and hiccups in about 10%1 of children receiving felbamate as adjunctive therapy. Esophagitis and increased appetite were reported in less than 1% of patients receiving felbamate.1 GI hemorrhage,27 hematemesis,27 gastritis,27 rectal hemorrhage,27 flatulence,27 gingival bleeding,27 acquired megacolon,27 ileus,27 intestinal obstruction,27 enteritis,27 ulcerative stomatitis,27 glossitis,27 and dysphagia27 also have been reported in patients receiving felbamate; however, a causal relationship to the drug has not been established.27 Pancreatitis also has occurred in patients receiving felbamate.27

Nervous System Effects

Adverse nervous system effects were among the most frequent adverse effects reported in adults and children receiving felbamate in controlled clinical trials.1,8,11,12,13,14,15,20 Adverse neurologic effects1,14,15 caused discontinuance of felbamate in about 1.5% of adults and children, and adverse psychologic effects1,14 caused discontinuance of the drug in about 2% of adults and 1% of children.1

Headache1,8,11,12,13,14,15,20 was the most frequent adverse nervous system effect of felbamate in adults, occurring in about 7% of those receiving monotherapy and about 37% of those receiving adjunctive therapy.1 Somnolence1,8,11,14,15,20 was another frequent adverse nervous system effect of the drug, occurring in about 48% of children and about 19% of adults receiving adjunctive therapy.1 Insomnia1,8,11,15,20 was reported in about 18% of adults and about 16% of children receiving felbamate as adjunctive therapy, and in about 9% of adults receiving the drug as monotherapy.1 Dizziness1,8,11,12,13,14 was another frequent adverse effect in adults, occurring in about 18% of those receiving adjunctive therapy.1 Fatigue1,8,11,13,14,15,20 occurred in about 17% of adults and about 10% of children receiving felbamate as adjunctive therapy, and in about 7% of adults receiving the drug as monotherapy.1 Nervousness1,8,11,15 was reported in about 7% of adults and about 16% of children receiving adjunctive therapy.1 Ataxia1,12,15,20 occurred in about 4% of adults and about 7% of children1 and abnormal gait1,15 in about 5% of adults and about 10% of children receiving felbamate as adjunctive therapy.1 Anxiety1,14 was reported in about 5% of adults receiving monotherapy or adjunctive therapy with felbamate.1

Tremor occurred in about 6%,1,11 depression in about 5%,1 paresthesia in about 4%,1 and stupor in about 3%1 of adults receiving felbamate as adjunctive therapy. Pain occurred in about 7% and abnormal thinking and emotional lability in about 7% of children receiving adjunctive therapy with the drug.1

Other adverse nervous effects that occurred in at least 1% of adults and children receiving felbamate included asthenia, malaise, agitation, psychologic disturbance, and aggressive reaction.1 Hallucination, euphoria, and migraine occurred in less than 1% of patients receiving the drug.1

Attempted suicide has occurred in less than 1% of patients receiving felbamate.38 Patients receiving anticonvulsants may have an increased risk of suicidal behavior or ideation.35,37,39,40 (See Cautions: Precautions and Contraindications.)

Delusion,38 manic reaction,38 paranoid reaction,38 apathy,38 confusion,38 impaired concentration,38 and psychosis38 have been reported in patients receiving felbamate. Paralysis,38 mononeuritis,38 encephalopathy,38 nystagmus,38 choreoathetosis,38 extrapyramidal disorder,38 dyskinesia,38 dysarthria,38 and status epilepticus38 are other adverse nervous system effects reported in patients receiving felbamate. In addition, cerebrovascular disorder,38 cerebral edema,38 coma,38 and respiratory depression38 have been reported in patients receiving the drug.

Dermatologic and Sensitivity Reactions

Rash1,11 occurred in about 4% of adults and about 10% of children receiving felbamate as adjunctive therapy, and in about 3% of adults receiving the drug as monotherapy in controlled clinical trials.1 Rash1,11 caused discontinuance of the drug in about 1% of adults and children.1 Acne and facial edema were reported in about 3% of adults receiving felbamate as monotherapy.1 Pruritus occurred in at least 1%, urticaria or bullous eruption in less than 1%, and allergic photosensitivity reaction,1 buccal mucous membrane swelling,1 or Stevens-Johnson syndrome (SJS)1,20 in less than 0.1% of adults and children receiving felbamate.1 Anaphylactoid reaction was reported in less than 0.1% of patients receiving felbamate.1 Adverse dermatologic effects caused discontinuance of felbamate in 1.5% of adults and 1.4% of children.1 Abnormal body odor,38 sweating,38 lichen planus,38 livedo reticularis,38 alopecia,38 and toxic epidermal necrolysis (TEN)38 also have been reported in patients receiving felbamate, usually as adjunctive therapy;38 however, a causal relationship to the drug has not been established.38

Cardiovascular Effects

Chest pain (substernal) occurred in about 3% of adults receiving felbamate as adjunctive therapy in controlled clinical trials.1 Palpitation and tachycardia occurred in at least 1% and supraventricular tachycardia in less than 0.1% of adults receiving the drug.1 Increases in heart rate (up to 5 beats/minute) may occur in adults receiving felbamate but usually are not clinically important.1 Other adverse cardiac effects that occurred in patients receiving felbamate, usually as adjunctive therapy, include atrial fibrillation,38 atrial arrhythmia,38 bradycardia,38 cardiac arrest,38 torsades de pointes,38 cardiac failure,38 hypotension,38 hypertension,38 and flushing.38 Thrombophlebitis,38 ischemic necrosis,38 gangrene,38 peripheral ischemia,38 and Henoch-Schönlein purpura (vasculitis)38 also have been reported in patients receiving felbamate.

Respiratory Effects

Upper respiratory tract infection1,11,15 occurred in about 5% of adults and about 45% of children receiving felbamate as adjunctive therapy, and in about 9% of adults receiving the drug as monotherapy in controlled clinical trials.1 Pharyngitis occurred in about 3% of adults and about 10% of children receiving felbamate as adjunctive therapy.1 Rhinitis1,15 was reported in about 7% of adults receiving felbamate as monotherapy,1 and sinusitis1 was reported in about 4% of adults receiving the drug as adjunctive therapy.1 Coughing was reported in about 7% of children receiving felbamate as adjunctive therapy.1 Influenza-like symptoms occurred in at least 1% of adults and children receiving the drug.1 Dyspnea,38 pneumonia,38 pneumonitis,38 hypoxia,38 epistaxis,38 pleural effusion,38 respiratory insufficiency,38 pulmonary hemorrhage,38 and asthma38 also have been reported in patients receiving felbamate, usually as adjunctive therapy.38

Ocular and Otic Effects

Diplopia1,11,12,13 occurred in about 3% of adults receiving felbamate as monotherapy and in about 6% receiving the drug as adjunctive therapy in controlled clinical trials.1 Visual abnormalities (e.g., blurred vision)1,12,13 occurred in about 5% of adults1 and miosis1,13 in about 7% of children receiving felbamate as adjunctive therapy.1 Hemianopia27 and conjunctivitis27 have been reported in patients receiving felbamate, usually as adjunctive therapy.

Otitis media occurred in about 3% of adults receiving felbamate as monotherapy and in about 10% of children receiving the drug as adjunctive therapy.1 Decreased hearing has been reported in patients receiving felbamate, usually as adjunctive therapy.27

Musculoskeletal Effects

Myalgia occurred in about 3% of adults receiving felbamate as adjunctive therapy in controlled clinical trials.1 Dystonia occurred in less than 1% of adults and children receiving the drug.1 Arthralgia,27 muscle weakness,27 involuntary muscle contraction,27 and rhabdomyolysis27 also have been reported in patients receiving felbamate, usually as adjunctive therapy.

Genitourinary Effects

Urinary tract infection and intramenstrual bleeding occurred in about 3% of adults receiving felbamate as monotherapy in controlled clinical trials.1 Urinary incontinence was reported in about 7% of children receiving the drug as adjunctive therapy.1 Menstrual disorder,27 vaginal hemorrhage,27 hematuria,27 and urinary retention27 also have been reported in patients receiving felbamate, usually as adjunctive therapy.

Electrolyte and Metabolic Effects

Hypophosphatemia occurred in about 3% of adults receiving felbamate as monotherapy in controlled clinical trials.1 Hypokalemia, hyponatremia, or hypophosphatemia occurred in less than 1% and increased serum concentrations of creatine kinase (CK, creatine phosphokinase, CPK) occurred in less than 0.1% of adults and children receiving the drug.1 Hypernatremia,27 hypoglycemia,27 syndrome of inappropriate antidiuretic hormone (SIADH),27 hypomagnesemia,27 and dehydration27 also have been reported in patients receiving felbamate, usually as adjunctive therapy.

A decrease in body weight,1,8,11 averaging 5%,1 occurred in about 3% of adults and about 7% of children receiving felbamate in controlled clinical trials, and required discontinuance of the drug in about 1% of adults.1 An increase in body weight occurred in at least 1% of adults and children receiving felbamate.1

Renal Effects

Acute renal failure,27 hepatorenal syndrome,27 and nephrosis27 have been reported in patients receiving felbamate, usually as adjunctive therapy; however, a causal relationship to the drug has not been established.27

Other Adverse Effects

Fever1,15 occurred in about 3% of adults and about 23% of children receiving felbamate as adjunctive therapy.1 Neoplasm,27 sepsis,27 LE syndrome,27 sudden death,27 edema,27 hypothermia,27 and rigors27 have been reported in patients receiving felbamate, usually as adjunctive therapy.

Precautions and Contraindications

Patients should be informed that felbamate is associated with a risk of potentially fatal aplastic anemia and hepatic failure and that these conditions can occur at any time during therapy.40 (See introductory discussion in Cautions.) There is currently no reliable means to predict the likelihood of these adverse effects and no method of monitoring that has been shown to effectively prevent or reduce serious injury.22,26,31,40 However, early clinical changes may be detected with patient monitoring and laboratory testing (i.e., complete blood counts [CBCs] and serum transaminase concentrations).40 Patients receiving felbamate should be alert for any signs or symptoms of infection, bleeding, easy bruising, anemia (e.g., fatigue, weakness), or liver dysfunction (e.g., jaundice, anorexia, GI symptoms, malaise) and instructed to immediately report any such manifestations to their clinician.40

Felbamate, like any anticonvulsant, should be withdrawn slowly since abrupt discontinuance of the drug may precipitate seizures.40 To minimize the risk of adverse withdrawal effects, it has been recommended that felbamate dosage be decreased in increments that are one-third of the baseline daily dosage, at 4- to 5-day intervals; according to this schedule, therapy with the drug usually can be discontinued over a period of 8-10 days.19,23 If, in the clinician's judgment, abrupt discontinuance of the drug is necessary, felbamate therapy may be stopped without gradual decreases in dosage provided that the patient receives adequate dosage(s) of another anticonvulsant agent.23

In rare cases in which felbamate therapy is continued, clinicians are advised to monitor these patients carefully, although there is no evidence that even close monitoring with frequent CBCs and liver function tests can protect against the occurrence of aplastic anemia21,22,31,40 and/or acute hepatic failure.28,40 Ordinarily, felbamate therapy should not be initiated or continued in patients without expert hematologic consultation.19,40 Full hematologic evaluations should be performed before initiation of felbamate therapy, at frequent intervals during therapy, and for a substantial period of time following discontinuance of felbamate therapy.40 If any hematologic abnormality is detected during the course of felbamate therapy, immediate consultation with a hematologic expert is advised.40 If any evidence of bone marrow depression occurs in a patient receiving felbamate, therapy with the drug should be discontinued.40

Evaluation of hepatic function also should be performed before initiation of felbamate therapy; the drug should not be used in patients with preexisting hepatic impairment.40 Serum transaminase (ALT, AST) concentrations should be monitored prior to initiation of therapy and periodically thereafter (with precise schedule of monitoring based on clinician's judgment).40 If any hepatic abnormality (as indicated by increases in AST or ALT concentrations to 2 or more times the ULN, or by clinical manifestations) is detected during the course of felbamate therapy, the drug should be discontinued and not resumed.40 However, it is uncertain whether early withdrawal of felbamate therapy following initial signs of hepatic injury can reduce the risk of subsequent fulminant hepatic failure.28

An increased risk of suicidality (suicidal behavior or ideation) was observed in an analysis of studies using various anticonvulsants compared with placebo.35,37,39,40 The analysis included 199 randomized, placebo-controlled studies of 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain).35,37,40 The analysis revealed that patients receiving these anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%); this increased suicidality risk was observed as early as 1 week after beginning therapy and continued through 24 weeks.35,37,39,40 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative risk for suicidality was higher for patients with epilepsy compared with patients receiving anticonvulsants for other conditions.35,37,40

All patients who are currently receiving or beginning therapy with any anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior.35,37,39,40 Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality.40 Clinicians who prescribe felbamate or any other anticonvulsant must balance the risk for suicidality with the risk of untreated illness.35,40 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with an increased risk of morbidity and mortality and an increased risk of suicidal thoughts and behavior.40 If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician must consider whether these symptoms may be related to the illness being treated.40

Felbamate inhibits cytochrome P-450 (CYP) isoenzyme 2C19 and is a weak inducer of CYP3A4.44,265 Concomitant use with drugs (e.g., phenytoin, carbamazepine, phenobarbital, valproic acid, clobazam, clonazepam, estrogen, warfarin) metabolized by these isoenzymes can alter plasma concentrations of the concomitant drug.40,265 Therefore, dosage adjustments may be necessary during concomitant therapy.40

Felbamate is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.40 The drug also is contraindicated in patients who have demonstrated hypersensitivity reactions to other carbamates.40 Felbamate should not be used in patients with a history of any blood dyscrasia or hepatic dysfunction.40

Pediatric Precautions

Felbamate is indicated as adjunctive therapy for the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children 2-14 years of a 40 safety and efficacy of the drug for this indication in children younger than 2 years of age have not been established.40 Safety and efficacy of felbamate for other indications in children have not been established.40 However, the drug may be used for the treatment of partial seizures in adolescents 14 years of age or older.40

Geriatric Precautions

Safety and efficacy of felbamate in geriatric patients have not been evaluated systematically, and clinical trials did not include sufficient numbers of patients older than 65 years of age to determine whether they respond differently than younger patients.40 Other clinical experience has not identified any differences in responses between geriatric and younger patients.40 If felbamate is used in geriatric patients, the initial dosage usually should be at the low end of the dosage range and caution should be exercised since renal, hepatic, and cardiovascular dysfunction and concomitant disease or other drug therapy are more common in this age group than in younger patients.40

Mutagenicity and Carcinogenicity

No evidence of mutagenicity was demonstrated by felbamate in the Ames Salmonella microbial mutagen test, the CHO/HGPRT mammalian cell forward gene mutation assay, the sister chromatid exchange assay in CHO cells, or bone marrow cytogenetics assay.1

Studies to determine the carcinogenic potential of felbamate were performed in mice and rats.1 Mice received felbamate orally in dosages of 300, 600, and 1200 mg/kg daily for 92 weeks, while male rats received the drug orally in dosages of 30, 100, and 300 mg/kg and female rats received 10, 30, and 100 mg/kg daily for 104 weeks.1 The maximum dosages used in these studies produced steady-state plasma felbamate concentrations that were equal to or less than the steady-state plasma concentrations in patients with epilepsy receiving 3600 mg of the drug daily.1 There was an increase in hepatic cell adenomas in male and female mice receiving the high dosages as well as in female rats receiving the high dosages.1 Hepatic hypertrophy also was increased in a dose-related manner in mice, principally in males, but also in females.1 Hepatic hypertrophy was not found in female rats.1 The relationship between the occurrence of benign hepatocellular adenomas and the finding of liver hypertrophy resulting from hepatic enzyme induction has not been evaluated.1 There also was an increase in benign interstitial cell tumors of the testes in male rats receiving high dosages of felbamate.1 The relevance of these findings to humans is not known.1

As a result of the synthetic process involved in producing felbamate, the drug could contain small amounts of two known animal carcinogens: the genotoxic compound ethyl carbamate (urethane) and the nongenotoxic compound methyl carbamate.1 Theoretically, it is possible that a 50-kg patient receiving 3600 mg of felbamate could be exposed to up to 0.72 mcg of urethane and 1800 mcg of methyl carbamate.1 These daily doses of urethane and methyl carbamate are approximately 1/35,000 and 1/5500, respectively, on a mg/kg basis (1/10,000 and 1/1600, respectively, on a mg/m² basis) of the dose levels shown to be carcinogenic in rodents.1 Any presence of these two compounds in felbamate used in the lifetime carcinogenicity studies was inadequate to cause tumors.1

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits receiving felbamate doses of up to 13.9 and 4.2 times, respectively, the human daily dose of the drug on mg/kg basis (3 and less than 2 times, respectively, the human daily dose on a mg/m² basis) did not reveal evidence of teratogenicity;1 however, in rats, there was a decrease in pup weight and an increase in pup deaths during lactation.1 The cause of these deaths is not known.1 The dose at which there was no effect on rat pup mortality was 6.9 times the human dose on a mg/kg basis (1.5 times the human dose on a mg/m² basis).1 Felbamate crosses the placenta in rats.1 There are, however, no adequate and controlled studies to date using the drug in pregnant women,1 and the effect of felbamate on labor and delivery in humans also is not known.1 Felbamate should be used during pregnancy only when clearly needed.40

Women who are pregnant while receiving felbamate should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334; registry information also is available at [Web].40

Fertility

Reproduction studies in rats revealed no evidence of impaired fertility in males or females receiving oral felbamate dosages of up to 13.9 times the human total daily dosage of 3600 mg on a mg/kg basis (up to 3 times the human total daily dosage on a mg/m² basis).1

Lactation

Felbamate is distributed into milk.40,46 Since the potential effect in nursing infants is not known,40 some clinicians state that felbamate probably should not be used during breast-feeding.46

Description

Felbamate, a dicarbamate, is an anticonvulsant agent.1,3,4,5,20 Felbamate is structurally related to but pharmacologically distinct from meprobamate.3,5,7,20 Felbamate has a unique spectrum of activity compared with other currently available anticonvulsants.4,6

The exact mechanism of action of felbamate is not known, but available data suggest that the drug increases seizure threshold and reduces seizure spread.1,4,6,20 A predominant effect on any particular cell process has not been demonstrated to date, but felbamate appears to exhibit a spectrum of anticonvulsant activity that is pharmacologically distinct from other currently available agents.1,4,6,7,20 In animals, felbamate protects against seizures induced by electrical stimulation, suggesting that it would be effective in the management of tonic-clonic (grand mal) seizures and partial seizures.1,4,6 In animals, felbamate also protects against seizures induced by pentylenetetrazol, indicating that it may be effective in the management of absence (petit mal) seizures.1,4,6 Felbamate also protects against seizures in animals induced by picrotoxin,1,4,6 glutamate,1 or N -methyl-d,l-aspartic acid;1 it does not protect against seizures induced by bicuculline or strychnine.4,6

In vitro studies indicate that felbamate has weak inhibitory effects on binding at γ-aminobutyric acid (GABA) receptors and benzodiazepine receptors.1 The monocarbamate, p -hydroxy, and 2-hydroxy metabolites of felbamate appear to contribute little, if any, to the anticonvulsant action of the drug.1,4,6

Additional Information

SumMon^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications concerning potential drug interactions and/or laboratory test interferences and for information on acute toxicity.

1. Wallace Laboratories. Felbatol^® (felbamate) tablets and oral suspension prescribing information. Cranbury, NJ; 1993 Jul 31.

2. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 30, 1993. Rockville, MD; 1993 Jul.

3. Pugh CB, Garnett WR. Current issues in the treatment of epilepsy. Clin Pharm . 1991; 10:335-58. [PubMed 2049897]

4. Graves NM, Leppik IE. Antiepileptic medications in development. DICP . 1991; 25:978-86. [PubMed 1949977]

5. Brodie MJ, Porter RJ. New and potential anticonvulsants. Lancet . 1990; 336:425-6. [PubMed 1974955]

6. Anon. Felbamate. Phase III Prof . 1992; 2: 14-9.

7. Brodie MJ. Felbamate: a new antiepileptic drug. Lancet . 1993; 341:1445-6. [PubMed 8099147]

8. Sachdeo R, Kramer LD, Rosenberg A et al. Felbamate monotherapy` controlled trial in patients with partial onset seizures. Ann Neurol . 1992; 32:386-92. [PubMed 1416808]

9. Wilner AN. Efficacy of felbamate monotherapy. Ann Neurol . 1993; 33:661. [PubMed 8498849]

10. Sachdeo R. Efficacy of felbamate monotherapy. Ann Neurol . 1993; 33:661-2. [PubMed 8498849]

11. Faught E, Sachdeo RC, Remler MP et al. Felbamate monotherapy for partial-onset seizures: an active-control trial. Neurology . 1993; 43:688-92. [PubMed 8469323]

12. Leppik IE, Dreifuss FE, Pledger GW et al. Felbamate for partial seizures: results of a controlled clinical trial. Neurology . 1991; 41:1785-9. [PubMed 1944909]

13. Theodore WH, Raubertas RF, Porter RJ et al. Felbamate: a clinical trial for complex partial seizures. Epilepsia . 1991; 32:392-7. [PubMed 2044501]

14. Bourgeois B, Leppik IE, Sackellares JC et al. Felbamate: a double-blind controlled trial in patients undergoing presurgical evaluation of partial seizures. Neurology . 1993; 43:693-6. [PubMed 8469324]

15. The Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). N Engl J Med . 1993; 328:29-33. [PubMed 8347179]

16. Snodgrass SR. Felbamate therapy in the Lennox-Gastaut syndrome. N Engl J Med . 1993; 328:1641. [PubMed 8487814]

17. Ritter FJ. Felbamate therapy in the Lennox-Gastaut syndrome. N Engl J Med . 1993; 328:1641.

18. Pledger GW, Kramer LD. Clinical trials of investigational antiepileptic drugs: monotherapy designs. Epilepsia . 1991; 32:716-21. [PubMed 1915182]

19. Wallace, Princeton, NJ: Personal communication.

20. Anon. Felbamate. Med Lett Drugs Ther . 1993; 35:107-8. [PubMed 8232064]

21. Cruzan S. From the FDA electronic bulletin board: suspension of Felbatol use urged. Rockville, MD: Food and Drug Administration; 1994 Aug 1.

22. Costin JC. Dear doctor letter regarding recommendation for the immediate withdrawal of patients from treatment with Felbatol^® (felbamate). Cranbury, NJ: Wallace Laboratories; 1994 Aug 1.

23. Neumann E. Dear doctor letter regarding the recommended procedure for the discontinuation of Felbatol^® (felbamate). Cranbury, NJ: Wallace Laboratories; 1994 Aug 1.

24. Flanagan HP III. Dear pharmacist letter regarding suspension of Felbatol^® (felbamate) therapy. Cranbury, NJ: Wallace Laboratories; 1994 Aug.

25. Cruzan S. From the FDA electronic bulletin board: felbamate approved for epilepsy. Rockville, MD: Food and Drug Administration; 1993 Aug 2.

26. Costin JC. Dear doctor letter regarding revised prescribing information for Felbatol^®. Cranbury, NJ: Wallace Laboratories; 1994 Aug 26.

27. Wallace Laboratories. Felbatol^® (felbamate) tablets 400 mg and 600 mg and oral suspension 600 mg/5 mL prescribing information. Cranbury, NJ; 1994 Oct.

28. Costin JC. Dear doctor letter regarding recommendation for monitoring liver function tests in patients being treated with Felbatol^® (felbamate). Cranbury, NJ: Wallace Laboratories; 1994 Sep 21.

29. Cruzan S. FDA Talk Paper T94-46. Felbatol update. Rockville, MD: Food and Drug Administration; 1994 Sep 27.

30. Ahmad SR. Felbamate and aplastic anemia. Lancet . 1994; 344:465.

31. Nightingale SL. From the Food and Drug Administration: recommendation to immediately withdraw patients from treatment with felbamate. JAMA . 1994; 272:995. [PubMed 8089899]

32. Costin JC. Dear doctor letter regarding revised prescribing information for Felbatol^®. Cranbury, NJ: Wallace Laboratories; 1994 Oct 26.

33. Flanagan HP III. Dear pharmacist letter regarding revised prescribing information for Felbatol^®. Cranbury, NJ: Wallace Laboratories; 1994 Oct 26.

34. US Food and Drug Administration. Medwatch web site. 1999. [Web]

35. Food and Drug Administration. FDA Alert: Information for healthcare professionals: suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website. [Web]

37. Food and Drug Administration. FDA Alert: Suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website. [Web]

38. MedPointe Pharmaceuticals. Felbatol^® (felbamate) tablets 400 mg and 600 mg and oral suspension 600 mg/5 mL prescribing information. Somerset, NJ; 2002 Dec.

39. Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website. Accessed 2009 Oct 7. [Web]

40. Meda Pharmaceuticals Inc. Felbatol^® (felbamate) tablets and suspension prescribing information. Somerset, NJ; 2011 Nov

41. Taro Pharmaceuticals. Felbamate oral 600 mg/5 mL suspension prescribing information. Hawthorne, NY; 2017 Jun.

42. Alvogen. Felbamate tablets prescribing information. Pine Brook, NJ; 2018 Nov.

43. French J, Smith M, Faught E et al. Practice advisory: the use of felbamate in the treatment of patients with intractable epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology . 1999; 52:1540-5.

44. Hachad H, Ragueneau-Majlessi I, Levy RH. New antiepileptic drugs: review on drug interactions. Ther Drug Monit . 2002; 24:91-103.

45. Glue P, Banfield CR, Perhach JL et al. Pharmacokinetic interactions with felbamate. In vitro-in vivo correlation. Clin Pharmacokinet . 1997; 33:214-24. [PubMed 9314612]

46. Briggs GG, and Freeman RK. Drugs in pregnancy and lactation. 10th ed. Philadelphia, PA: Wolters Kluwer Health; 2015: 535.

258. . Drugs for epilepsy. Med Lett Drugs Ther . 2017; 59:121-130. [PubMed 28746301]

265. Johannessen SI, Landmark CJ. Antiepileptic drug interactions - principles and clinical implications. Curr Neuropharmacol . 2010; 8:254-67. [PubMed 21358975]