Total Cost
Free shipping on all orders

Powered by GeniusRx

felbamate 400 mg tablet generic felbatol

In stock Manufacturer ALVOGEN INC 47781055001
$3.57 / Tablet

Select Quantity

Prescription is required

Uses

In July 1993, felbamate (Felbatol) originally was approved by the US Food and Drug Administration (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. 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 children and has been designated an orphan drug by FDA for the treatment of this latter syndrome. However, because use of the drug has since been associated with marked increases in the incidences of aplastic anemia and acute hepatic failure, the manufacturer in conjunction with FDA warns that the drug should only be initiated or continued in the management of such seizures when, in the clinician's judgment, the patient's 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 anemia or acute hepatic failure. For patients already receiving the drug, the likelihood that abrupt withdrawal would pose an even greater risk than that of possible felbamate-associated aplastic anemia or acute hepatic failure also should be considered in the decision to discontinue therapy with the drug. Decisions about the potential benefits and risks of felbamate therapy generally should be made in consultation with appropriate hematologic and hepatic disease experts.(See Cautions.)

The manufacturer has notified pharmacists that felbamate is not being recalled and may continue to be dispensed in response to a bona fide physician prescription. The manufacturer states that felbamate will continue to be available in the US for those patients with severe, refractory seizure disorders in whom, in the opinion of the clinician, benefits of the drug outweigh the potential risk for aplastic anemia and hepatic failure. However, clinicians should prescribe felbamate only if therapy with the drug is absolutely necessary. Therapy with felbamate should be initiated or continued only after the risks associated with use of the drug have been discussed completely with the patient, parent, or guardian and written informed consent has been obtained; patient information/consent forms for felbamate may be obtained from the manufacturer or by photocopy reproduction of the form included in the manufacturer's labeling.

Clinicians and pharmacists interested in further information on felbamate should contact Meda Pharmaceuticals at 800-526-3840. All cases of aplastic anemia or acute hepatic failure associated with felbamate therapy should be reported promptly to Meda Pharmaceuticals at 800-526-3840 or to the FDA MedWatch program by phone (800-FDA-1088), by fax (800-FDA-0178), by the internet (http://www.fda.gov/Safety/MedWatch/), or by mail (MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787).

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. 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. 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. 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. 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; however, because of study design, no conclusions regarding comparative efficacy with valproic acid can be made.

Felbamate also may potentiate the anticonvulsant activity of other agents in the management of refractory partial seizures. 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. 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. 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.

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. Improvements in quality-of-life parameters (increased alertness and verbal responsiveness) also have been reported by parents or guardians in such children.

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.

Dosage and Administration

Administration

Felbamate is administered orally. 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; pharmacokinetic profiles of the tablet and oral suspension are similar. Felbamate tablets may be administered without regard to meals; however, the effect of food on GI absorption of felbamate from the oral suspension has not been evaluated.

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.(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. Felbamate should be withdrawn slowly because abrupt discontinuance of the drug may precipitate seizures.

When felbamate is used as initial monotherapy, therapy should begin with low dosages of the drug that are slowly increased. When felbamate is added to an anticonvulsant therapeutic regimen, the drug should be added gradually while the other anticonvulsant(s) is decreased gradually. When transferring patients from combination therapy to monotherapy with felbamate, dosages of felbamate should be increased gradually while dosages of other anticonvulsant agents are decreased gradually and discontinued.

While the manufacturer currently does not make specific dosage recommendations for geriatric patients, felbamate has not been evaluated systematically in those 65 years of age and older. If the drug 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.

The initial dosage of felbamate as monotherapy, during conversion to monotherapy, or in combination therapy for the management of seizure disorders in adults and children 14 years of age and older is 1.2 g daily administered in 3 or 4 divided doses.

In adults and children 14 years of age and older receiving felbamate as initial monotherapy, 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. If adequate seizure control has not been achieved and further increases in monotherapy dosage are considered clinically necessary, felbamate dosage may be titrated incrementally under close clinical supervision to a maximum of 3.6 g daily. Felbamate has not been evaluated systematically as initial monotherapy.

In adults and children 14 years of age and older being transferred from combination therapy to monotherapy with felbamate and in those receiving felbamate as a component of combination therapy with other anticonvulsant agents, felbamate dosage may be increased by 1.2-g daily increments at weekly intervals to a maximum of 3.6 g daily given in 3 or 4 divided doses. As felbamate replaces an existing anticonvulsant therapeutic regimen, the dosage(s) of the other anticonvulsant(s) is gradually reduced and discontinued. As felbamate is added to an anticonvulsant regimen, the dosage(s) of the other anticonvulsant(s) must be reduced initially by at least 20%; overall reductions of 20-33% in dosage(s) of concomitant anticonvulsant(s) may be necessary to avoid adverse effects caused by drug interactions.

The maximum dosage of felbamate for adults and children 14 years of age and older recommended by the manufacturer is 3.6 g daily in 3 or 4 divided doses. More rapid titration of felbamate dosage (e.g., increasing dosage to 3.6 g daily over a 3-day period) than that currently suggested by the manufacturer occasionally has been employed.

The usual initial dosage of felbamate as a component of combination 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. Dosage may be increased by 15 mg/kg daily at weekly intervals to a maximum dosage of 45 mg/kg daily administered in 3 or 4 divided doses. As felbamate is added to the anticonvulsant regimen, the dosage(s) of other anticonvulsant(s) must be decreased initially by at least 20%; further reductions in dosage(s) of concomitant anticonvulsant(s) may be necessary as felbamate dosage is increased.

Dosage in Renal and Hepatic Impairment

The effects of renal or hepatic impairment on the pharmacokinetics of felbamate have not been evaluated. The manufacturer currently makes no specific recommendations for dosage adjustment in patients with renal and/or hepatic impairment.

Cautions

Because use of felbamate has been associated with marked increases in the incidences of aplastic anemia and acute hepatic failure, the manufacturer in conjunction with the US Food and Drug Administration (FDA) warns that 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 anemia or acute hepatic failure. For patients already receiving the drug, the likelihood that abrupt withdrawal would pose an even greater risk than that of possible felbamate-associated aplastic anemia or acute hepatic failure also should be considered in the decision to discontinue therapy with the drug. Decisions about the potential benefits and risks of felbamate therapy generally should be made in consultation with appropriate hematologic and hepatic disease experts.(See Uses and see Cautions: Precautions and Contraindications.)

At least 21 reported cases (20 of which occurred in the US) of aplastic anemia have developed in association with felbamate therapy. The rate of aplastic anemia cases currently reported with the drug appears to be at least 40-100 times higher than the expected rate of 2-5 cases per million untreated individuals per year. However, because the onset of felbamate-induced aplastic anemia typically is delayed for weeks to months after initiation of the drug and a substantial fraction of patients had felbamate therapy withdrawn for other reasons prior to this period, the absolute rate of this anemia associated with felbamate probably is higher than the currently reported rate of 1 case per 5000 patients per year. Based on this probability, the manufacturer estimates that the actual risk of aplastic anemia associated with felbamate therapy may be as high as 1 case per 2000 patients (500 cases per million patients) per year or more among those who remain on the drug for longer than a few weeks. While postmarketing surveillance usually captures only a fraction of incident cases, the syndrome is still relatively rare, and no cases were observed during premarket testing in which more than 1600 patients received felbamate therapy. All reports of aplastic anemia associated with felbamate therapy to date have occurred in patients receiving the drug for at least 5 weeks.

Of the 21 patients who developed aplastic anemia while receiving felbamate therapy, 5 (all from the US) have died. 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%. 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. Although most reported cases have been in white females, risk factors for the development of aplastic anemia in patients receiving felbamate therapy have not been identified. 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. Therefore, the manufacturer recommends that felbamate therapy be discontinued in any patient receiving the drug and alternative therapy initiated as necessary, unless in the clinician's judgment continued felbamate therapy outweighs the risk for aplastic anemia.

At least 10 reported cases (all from the US) of acute hepatic failure have developed in association with felbamate therapy. The rate of acute hepatic failure cases currently reported with the drug greatly exceeds the expected incidence rate of about 2000 cases per year. These cases were reported as part of the ongoing postmarketing surveillance program, and no cases of acute hepatic failure were observed during premarket testing. All reports of acute hepatic failure associated with felbamate therapy to date have occurred in patients receiving the drug for at least 2 weeks.

Of the 10 patients who developed acute hepatic failure while receiving felbamate therapy, 4 have died, and 1 has received a liver transplant. Whether preexisting hepatic impairment increases the risk of fulminant hepatic failure is unknown; however, the manufacturer recommends that all patients be evaluated for evidence of hepatic impairment prior to initiation of felbamate therapy, and use of the drug is not recommended in patients with preexisting hepatic abnormalities. Other risk factors for the development of acute hepatic failure in patients receiving felbamate have not been identified. 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.

Other adverse effects of felbamate usually are mild to moderate in severity and self-limiting, infrequently requiring dosage adjustment. GI tract and nervous system effects are the most frequent adverse effects of felbamate and the adverse effects most frequently requiring discontinuance of the drug. 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. In children, the most frequent adverse effects of the drug during adjunctive therapy are anorexia, vomiting, insomnia, headache, and somnolence. 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.

The frequency of most adverse effects associated with felbamate appears to be lower during monotherapy than adjunctive therapy. 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. 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. 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.

Hematologic Effects

Use of felbamate has been associated with a marked increase in the incidence of aplastic anemia; at least 5 deaths have occurred in patients who developed aplastic anemia while receiving felbamate.(See introductory discussion in Cautions and Cautions: Precautions and Contraindications.)

Purpura occurred in about 13% and leukopenia in about 6% of children receiving felbamate as adjunctive therapy in controlled clinical trials. Lymphadenopathy, leukopenia, granulocytopenia, leukocytosis, and thrombocytopenia occurred in less than 1% and agranulocytosis, positive antinuclear factor test results, and qualitative platelet disorder occurred in less than 0.1% of adults and children receiving felbamate. Increased and decreased prothrombin time, anemia, hypochromic anemia, pancytopenia, and hemolytic uremic syndrome 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; at least 4 deaths have occurred in patients who developed acute hepatic failure while receiving felbamate.(See introductory discussion in Cautions and Cautions: Precautions and Contraindications.)

Increased serum concentrations of ALT (SGPT) occurred in about 5% of adults receiving felbamate as monotherapy and about 4% receiving the drug as adjunctive therapy in controlled clinical trials. Increased serum concentrations of AST (SGOT) occurred in at least 1%, increased serum concentrations of LDH or alkaline phosphatase in less than 1%, and increased serum concentrations of γ-glutamyltransferase (GT, γ-glutamyltranspeptidase, GGTP) in less than 0.1% of patients receiving felbamate. Hepatitis, hyperammonemia, and jaundice 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. In adults, adverse GI effects were the most common adverse effects resulting in discontinuance of the drug, which occurred in 4.3% of patients.

Nausea 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. Anorexia occurred in about 19% of adults and about 55% of children receiving felbamate as adjunctive therapy, and required discontinuance in 1.6% of adults; 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. Vomiting 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. Dyspepsia 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. Constipation 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. Diarrhea occurred in about 5% of adults receiving felbamate as monotherapy or adjunctive therapy. Abdominal pain was reported in about 5% of adults, dry mouth in about 3% of adults, taste perversion in about 6% of adults, and nausea in about 7% and hiccups in about 10% of children receiving felbamate as adjunctive therapy. Esophagitis and increased appetite were reported in less than 1% of patients receiving felbamate. GI hemorrhage, hematemesis, gastritis, rectal hemorrhage, flatulence, gingival bleeding, acquired megacolon, ileus, intestinal obstruction, enteritis, ulcerative stomatitis, glossitis, and dysphagia also have been reported in patients receiving felbamate; however, a causal relationship to the drug has not been established. Pancreatitis also has occurred in patients receiving felbamate.

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. Adverse neurologic effects caused discontinuance of felbamate in about 1.5% of adults and children, and adverse psychologic effects caused discontinuance of the drug in about 2% of adults and 1% of children.

Headache 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. Somnolence was another frequent adverse nervous system effect of the drug, occurring in about 48% of children and about 19% of adults receiving adjunctive therapy. Insomnia 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. Dizziness was another frequent adverse effect in adults, occurring in about 18% of those receiving adjunctive therapy. Fatigue 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. Nervousness was reported in about 7% of adults and about 16% of children receiving adjunctive therapy. Ataxia occurred in about 4% of adults and about 7% of children and abnormal gait in about 5% of adults and about 10% of children receiving felbamate as adjunctive therapy. Anxiety was reported in about 5% of adults receiving monotherapy or adjunctive therapy with felbamate.

Tremor occurred in about 6%, depression in about 5%, paresthesia in about 4%, and stupor in about 3% 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.

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. Hallucination, euphoria, and migraine occurred in less than 1% of patients receiving the drug.

Attempted suicide has occurred in less than 1% of patients receiving felbamate. FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants, including felbamate, and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).(See Cautions: Precautions and Contraindications.)

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

Dermatologic and Sensitivity Reactions

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

Cardiovascular Effects

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

Respiratory Effects

Upper respiratory tract infection 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. Pharyngitis occurred in about 3% of adults and about 10% of children receiving felbamate as adjunctive therapy. Rhinitis was reported in about 7% of adults receiving felbamate as monotherapy, and sinusitis was reported in about 4% of adults receiving the drug as adjunctive therapy. Coughing was reported in about 7% of children receiving felbamate as adjunctive therapy. Influenza-like symptoms occurred in at least 1% of adults and children receiving the drug. Dyspnea, pneumonia, pneumonitis, hypoxia, epistaxis, pleural effusion, respiratory insufficiency, pulmonary hemorrhage, and asthma also have been reported in patients receiving felbamate, usually as adjunctive therapy.

Ocular and Otic Effects

Diplopia occurred in about 3% of adults receiving felbamate as monotherapy and in about 6% receiving the drug as adjunctive therapy in controlled clinical trials. Visual abnormalities (e.g., blurred vision) occurred in about 5% of adults and miosis in about 7% of children receiving felbamate as adjunctive therapy. Hemianopia and conjunctivitis 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. Decreased hearing has been reported in patients receiving felbamate, usually as adjunctive therapy.

Musculoskeletal Effects

Myalgia occurred in about 3% of adults receiving felbamate as adjunctive therapy in controlled clinical trials. Dystonia occurred in less than 1% of adults and children receiving the drug. Arthralgia, muscle weakness, involuntary muscle contraction, and rhabdomyolysis 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. Urinary incontinence was reported in about 7% of children receiving the drug as adjunctive therapy. Menstrual disorder, vaginal hemorrhage, hematuria, and urinary retention 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. 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. Hypernatremia, hypoglycemia, syndrome of inappropriate antidiuretic hormone (SIADH), hypomagnesemia, and dehydration also have been reported in patients receiving felbamate, usually as adjunctive therapy.

A decrease in body weight, averaging 5%, 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. An increase in body weight occurred in at least 1% of adults and children receiving felbamate.

Renal Effects

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

Other Adverse Effects

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

Precautions and Contraindications

The manufacturer recommends that felbamate therapy be discontinued in any patient receiving the drug and alternative therapy initiated as necessary, unless in the clinician's judgment continued felbamate therapy outweighs the risk for aplastic anemia or acute hepatic failure. Risk factors for the development of aplastic anemia in patients receiving felbamate therapy have not been identified. Whether preexisting hepatic impairment increases the risk of fulminant hepatic failure is unknown; however, the manufacturer recommends that all patients be evaluated for evidence of hepatic impairment prior to initiation of felbamate therapy, and use of the drug is not recommended in patients with preexisting hepatic abnormalities. Other risk factors for the development of acute hepatic failure in patients receiving felbamate have not been identified. Whether age, 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 or acute hepatic failure in patients receiving felbamate remains to be established.

While the manufacturer states that withdrawal effects have not been reported to date in patients who discontinued felbamate therapy after 7 or more years of treatment, felbamate, like any anticonvulsant, should be withdrawn slowly since abrupt discontinuance of the drug may precipitate seizures. Therefore, patients should be advised not to discontinue felbamate therapy without consulting their clinician. To minimize the risk of adverse withdrawal effects, felbamate dosage may 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. 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.

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 complete blood counts (CBCs) and liver function tests can protect against the occurrence of aplastic anemia and/or acute hepatic failure in such patients. Ordinarily, felbamate therapy should not be initiated or continued in patients without expert hematologic consultation. 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. CBCs, including platelet and reticulocyte counts, should be performed prior to initiation of therapy with the drug. If any hematologic abnormality is detected during the course of felbamate therapy, immediate consultation with a hematologic expert is advised. If any evidence of bone marrow depression occurs in a patient receiving felbamate, therapy with the drug should be discontinued.

Evaluation of hepatic function also should be performed before initiation of felbamate therapy, and use of the drug is not advised in patients with preexisting hepatic impairment. The manufacturer currently recommends that serum hepatic aminotransferase (ALT, AST) and bilirubin concentrations be monitored prior to initiation of, and every 1-2 weeks during, felbamate therapy. If any hepatic abnormality is detected during the course of felbamate therapy, the drug should be discontinued immediately. 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.

FDA has informed healthcare professionals about an increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants compared with placebo. FDA's analysis included 199 randomized, placebo-controlled studies of 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) involving over 43,000 patients 5 years of age or older; the studies evaluated the effectiveness of the anticonvulsants in epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain). 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 one week after beginning therapy and continued through 24 weeks. The results were generally consistent among the 11 drugs studied. In addition, patients who were treated for epilepsy, psychiatric disorders, and other conditions were all found to be at increased risk for suicidality when compared with placebo; there did not appear to be a specific demographic subgroup of patients to which the increased risk could be attributed. However, the relative risk for suicidality was found to be higher in patients with epilepsy compared with patients who were given one of the drugs for psychiatric or other conditions.

Based on the current analysis of the available data, FDA recommends that all patients who are currently receiving or beginning therapy with any anticonvulsant for any indication be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior. Symptoms such as anxiety, agitation, hostility, mania, and hypomania may be precursors to emerging suicidality. Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality so that they are aware and able to notify their clinician of any unusual behavioral changes. Patients, family members, and caregivers also should be advised not to make any changes to the anticonvulsant regimen without first consulting with the responsible clinician. They should pay close attention to any day-to-day changes in mood, behavior, and actions; since changes can happen very quickly, it is important to be alert to any sudden differences. In addition, patients, family members, and caregivers should be aware of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions). If these or any new and worrisome behaviors occur, the responsible clinician should be contacted immediately. FDA also recommends that clinicians who prescribe felbamate or any other anticonvulsant balance the risk for suicidality with the risk of untreated illness. 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. If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician must consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Because steady-state plasma concentrations of concomitantly administered anticonvulsants may be altered in patients receiving combination therapy including felbamate, monitoring of plasma concentrations of other anticonvulsant agents and appropriate adjustment of felbamate and/or other anticonvulsant dosage may be necessary during concomitant therapy; the value of monitoring plasma concentrations of felbamate has not been established. Specialized references and the manufacturer's labeling should be consulted for specific recommendations. Although clinical trials indicate that routine monitoring of laboratory parameters is not necessary for safe use of felbamate, clinicians should exercise clinical judgment regarding monitoring of laboratory parameters during therapy with the drug.

Patients receiving felbamate should be instructed to take the drug only as prescribed and to store the drug in its tightly closed container at room temperature away from excessive heat, direct sunlight, moisture, and children.

Because of the possibility of increasing seizure frequency, anticonvulsant drugs, including felbamate, should not be discontinued suddenly.

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

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 age; safety and efficacy of the drug for this indication in children younger than 2 years of age have not been established. Safety and efficacy of felbamate for other indications in children have not been established.

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. Other clinical experience has not identified any differences in responses between geriatric and younger patients. 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.

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.

Studies to determine the carcinogenic potential of felbamate were performed in mice and rats. 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. 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. 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. Hepatic hypertrophy also was increased in a dose-related manner in mice, principally in males, but also in females. Hepatic hypertrophy was not found in female rats. The relationship between the occurrence of benign hepatocellular adenomas and the finding of liver hypertrophy resulting from hepatic enzyme induction has not been evaluated. There also was an increase in benign interstitial cell tumors of the testes in male rats receiving high dosages of felbamate. The relevance of these findings to humans is not known.

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. 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. 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/m basis) of the dose levels shown to be carcinogenic in rodents. Any presence of these two compounds in felbamate used in the lifetime carcinogenicity studies was inadequate to cause tumors.

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/m basis) did not reveal evidence of teratogenicity; however, in rats, there was a decrease in pup weight and an increase in pup deaths during lactation. The cause of these deaths is not known. 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/m basis). Felbamate crosses the placenta in rats. There are, however, no adequate and controlled studies to date using the drug in pregnant women, and the effect of felbamate on labor and delivery in humans also is not known. Placental disorder, fetal death, microcephaly, genital malformation, and sudden infant death syndrome (SIDS) have been reported with felbamate, usually when used as adjunctive therapy; however, a causal relationship to the drug has not been established. Felbamate should be used during pregnancy only when clearly needed.

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/m basis).

Lactation

Felbamate is distributed into milk. Since the potential effect in nursing infants is not known, felbamate should be used with caution in nursing women.

Write Your Own Review

Your meds on autopilot. Forever.