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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(FEL ba mate)
Generic Available (U.S.)
Yes
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM263034.pdf, must be dispensed with this medication.
Prescribing and Access Restrictions
A patient “informed consent” form should be completed and signed by the patient and physician. Copies are available from MEDA Pharmaceuticals by calling 800-526-3840.
Brand Names: U.S.
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Not as a first-line antiepileptic treatment; only in those patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed acceptable in light of the benefits conferred by its use. Patient must be fully advised of risk and provide signed written informed consent. Felbamate can be used as either monotherapy or adjunctive therapy in the treatment of partial seizures (with and without generalization) and in adults with epilepsy. Used as adjunctive therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children.
Pregnancy Risk Factor
C
Pregnancy Considerations
There are no adequate and well-controlled studies in pregnant women. Postmarketing case reports in humans include fetal death, genital malformation, anencephaly, encephalocele, and placental disorder.Patients exposed to felbamate during pregnancy are encouraged to enroll themselves into the AED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.
Lactation
Enters breast milk/not recommended
Breast-Feeding Considerations
Rat studies show a decreased weight and increased death in nursing pups. Felbamate has been detected in human milk. Adverse effects in human infants is unknown.
Contraindications
Hypersensitivity to felbamate any component of the formulation; or known sensitivity to other carbamates; history of any blood dyscrasia; hepatic dysfunction
Warnings/Precautions
Boxed warnings:
• Aplastic anemia: See “Concerns related to adverse effects” below.
• Hepatic failure: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Aplastic anemia: [U.S. Boxed Warning]: Felbamate is associated with a significant increased risk of aplastic anemia. Risk may be more than 100 fold greater than in untreated population. Current estimates of fatality are 20% to 30%, but higher rates (up to 70%) have been reported in the past. Aplastic anemia can develop at any point during therapy and for an unknown period of time after discontinuation of therapy. It is not known if dose, duration therapy, or concomitant medication use affects risk. Routine blood monitoring may be helpful in detecting hematologic changes before any clinical onset of signs/symptoms of the disease, however, aplastic anemia often develops without any prior indication or warnings. Discontinue use if any evidence of bone-marrow suppression occurs.
• Hepatic failure: [U.S. Boxed Warning]: Has been associated with rare cases of hepatic failure (estimated >6 cases per 75,000 patients per year). Of the cases reported in the literature, 67% have resulted in fatality or liver transplant. Onset may or may not be preceded by prodromal symptoms. It is not known whether dose, duration of therapy, or concomitant medication use affects risk. Monitoring of serum transaminases has not been demonstrated to prevent serious hepatic injury, however, early diagnosis and drug withdrawal may improve the likelihood of recovery. Obtain baseline transaminase levels and periodically thereafter; discontinue use if transaminase levels increase to ≥2 times the upper limit of normal or with signs/symptoms suggesting hepatic failure. Therapy should not be initiated or reintroduced in patients with evidence of hepatic damage or who discontinue use for any reason.
• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.
Disease-related concerns:
• Renal impairment: Use with caution in renal impairment; dose adjustment recommended.
Other warnings/precautions:
• Patient education: Patients should be thoroughly educated on the signs/symptoms of aplastic anemia and of hepatic failure prior to starting therapy. The patient or parent/guardian of the patient must provide written informed consent documenting the discussion of risks involved with therapy.
• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.
Adverse Reactions
>10%:
Central nervous system: Somnolence (children 48%; adults 19%), headache (children 7%; adults 7% to 37%), fever (children 23%; adults 3%), dizziness (18%), insomnia (9% to 18%), fatigue (7% to 17%), nervousness (7% to 16%)
Dermatologic: Purpura (children 13%)
Gastrointestinal: Anorexia (children 55%; adults 19%), vomiting (children 39%; adults 9% to 17%), nausea (children 7%; adults 34%), constipation (7% to 13%), dyspepsia (7% to 12%)
Respiratory: Upper respiratory infection (children 45%; adults 5% to 9%)
1% to 10%:
Cardiovascular: Chest pain (3%), facial edema (3%), palpitation (≥1%), tachycardia (≥1%)
Central nervous system: Nervousness (7% to 16%), abnormal thinking (7%), emotional lability (children 7%), ataxia (4% to 7%), anxiety (5%), depression (5%), stupor (3%), malaise (≥1%), agitation (≥1%), psychological disturbances (≥1%), aggressive reaction (≥1%), euphoria (≤1%), hallucination (≤1%), migraine (≤1%), suicide attempt (≤1%)
Dermatologic: Skin rash (children 10%; adults 3% to 4%), acne (3%), pruritus (≥1%), bullous eruption (≤1%), urticaria (≤1%)
Endocrine and metabolic: Hypophosphatemia (≤1% to 3%), intramenstrual bleeding (3%), hypokalemia (≤1%), hyponatremia (≤1%)
Gastrointestinal: Hiccup (children 10%), weight loss (3% to 7%), taste perversion (6%), abdominal pain (5%), diarrhea (5%), xerostomia (3%), weight gain (≥1%), appetite increased (≤1%), esophagitis (≤1%)
Genitourinary: Urinary tract infection (3%)
Hematologic: Leukopenia (1% to 7%), granulocytopenia (≤1%), leukocytosis (≤1%), lymphadenopathy (≤1%), thrombocytopenia (≤1%)
Hepatic: Liver function tests increased (1% to 4%), alkaline phosphatase increased (≤1%)
Neuromuscular & skeletal: Abnormal gait (children 10%; adults 5%), pain (children 7%), tremor (6%), paresthesia (4%), myalgia (3%), weakness (≥1%), dystonia (≤1%)
Ocular: Miosis (7%), diplopia (3% to 6%), abnormal vision (5%)
Otic: Otitis media (children 10%; adults 3%)
Respiratory: Pharyngitis (children 10%; adults 3%), cough (children 7%), rhinitis (7%), sinusitis (4%)
Miscellaneous: Flu-like syndrome (≥1%), lymphadenopathy (≥1%)
<1%, postmarketing, and/or case reports: Acute renal failure, agranulocytosis, allergic reaction, alopecia, anaphylactoid reaction, anemia, apathy, aplastic anemia, asthma exacerbation, atrial arrhythmia, atrial fibrillation, body odor, bradycardia, buccal mucous membrane swelling, cardiac arrest, cardiac failure, cerebrovascular disorder, cerebral edema, choreoathetosis, coagulation disorder, coma, concentration impaired, confusion, CPK increased, delusion, diaphoresis, DIC, dysphagia, dyspnea, dysarthria, dyskinesia, dysuria, embolism, encephalopathy, enteritis, eosinophilia, epistaxis, extrapyramidal disorder, fetal effects (anencephaly, death, encephalocele, genital malformations), flatulence, flushing, gastric ulcer, gastritis, gastroesophageal reflux, GI hemorrhage, gingival bleeding, glossitis, hematemesis, hematuria, hemianopsia, hemolytic anemia, Henoch-Schönlein vasculitis, hepatic failure, hepatitis, hepatorenal syndrome, hyperammonemia, hyper-/hypoglycemia, hyper-/hypotension, hypernatremia, hypocalcemia, hypomagnesemia, hypoxia, ileus, ischemic necrosis, jaundice, leukemia, lichen planus, livedo reticularis, manic reaction, mononeuritis, nephrosis, nystagmus, pancreatitis, pancytopenia, paralysis, paranoid reaction, peripheral ischemia, photosensitivity, platelet disorder, pleural effusion, pneumonitis, psychosis, pulmonary hemorrhage, rectal hemorrhage, renal function abnormal, respiratory depression, rhabdomyolysis, SIADH, Stevens-Johnson syndrome, sudden death, suicidal behavior/ideation, SVT, thrombophlebitis, torsade de pointes, toxic epidermal necrolysis, ulcerative stomatitis, urinary retention, urticaria, vaginal hemorrhage
Metabolism/Transport Effects
Substrate of CYP2E1 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2C19 (weak); Induces CYP3A4 (weak/moderate)
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double aripiprazole dose when initiating concomitant therapy with a CYP3A4 inducer (e.g., carbamazepine). Monitor response and adjust aripiprazole dose as clinically indicated. If CYP3A4 inducer is discontinued, reduce aripiprazole dose to 10-15 mg/day. Risk D: Consider therapy modification
Barbiturates: May decrease the serum concentration of Felbamate. Felbamate may increase the serum concentration of Barbiturates. Management: Monitor for elevated barbiturate concentrations/toxicity if felbamate is initiated/dose increased, or reduced concentrations/effects if felbamate is discontinued/dose decreased. Refer to phenobarbital dosing guidelines for patients receiving that agent. Risk C: Monitor therapy
CarBAMazepine: May decrease the serum concentration of Felbamate. Felbamate may decrease the serum concentration of CarBAMazepine. Management: In patients receiving carbamazepine, initiate felbamate at 1200 mg/day in divided doses 3-4 times daily while reducing carbamazepine dose by 20%. Monitor for reduced concentrations/effects of both drugs. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
Contraceptives (Estrogens): Felbamate may decrease the serum concentration of Contraceptives (Estrogens). Contraceptive failure is possible. Management: Use of a nonhormonal contraceptive is recommended. Risk D: Consider therapy modification
Contraceptives (Progestins): Felbamate may decrease the serum concentration of Contraceptives (Progestins). Management: Contraceptive failure is possible. Use of an alternative, nonhormonal method of contraception is recommended. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Cyproterone: May decrease the serum concentration of CYP2E1 Substrates. Risk C: Monitor therapy
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Divalproex: Felbamate may increase the serum concentration of Divalproex. Management: In patients receiving divalproex, initiate felbamate at 1200 mg/day in divided doses 3-4 times daily and reduce divalproex dose by 20%. Monitor for increased valproate concentrations/effects and decreased felbamate concentrations/effects. Risk D: Consider therapy modification
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Fosphenytoin: Felbamate may increase the serum concentration of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Felbamate. Management: Decreased phenytoin dose will likely be needed when adding felbamate; some reports suggest an empiric 20% decrease in phenytoin dose. Additional reductions may be needed if felbamate dose is increased or as otherwise guided by monitoring. Risk D: Consider therapy modification
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Ketorolac (Nasal): May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Ketorolac (Systemic): May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
PHENobarbital: Felbamate may increase the serum concentration of PHENobarbital. PHENobarbital may decrease the serum concentration of Felbamate. Management: In patients receiving phenobarbital, initiate felbamate at 1200 mg/day in divided doses 3-4 times daily and reduce phenobarbital dose by 20%. Monitor for increased phenobarbital concentrations/effects and decreased felbamate concentrations/effects. Risk D: Consider therapy modification
Phenytoin: Felbamate may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Felbamate. Management: Decreased phenytoin dose will likely be needed when adding felbamate; some reports suggest an empiric 20% decrease in phenytoin dose. Additional reductions may be needed if felbamate dose is increased or as otherwise guided by monitoring. Risk D: Consider therapy modification
Primidone: Felbamate may increase serum concentrations of the active metabolite(s) of Primidone. Specifically, phenobarbital concentrations may increase. Primidone may decrease the serum concentration of Felbamate. Management: In patients receiving primidone, initiate felbamate at 1200 mg/day in divided doses 3-4 times daily and reduce primidone dose by 20%. Monitor for increased phenobarbital concentrations/effects and decreased felbamate concentrations/effects. Risk D: Consider therapy modification
Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Valproic Acid: Felbamate may increase the serum concentration of Valproic Acid. Management: In patients receiving valproic acid, initiate felbamate at 1200 mg/day in divided doses 3-4 times daily and reduce valproic acid dose by 20%. Monitor for increased valproate concentrations/effects and decreased felbamate concentrations/effects. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Food: Food does not affect absorption.
Herb/Nutraceutical: Avoid evening primrose (seizure threshold decreased).
Storage
Store in tightly closed container at controlled room temperature of 20°C to 25°C (68°F to 77°F).
Mechanism of Action
Mechanism of action is unknown but has properties in common with other marketed anticonvulsants; has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding, and is devoid of activity at the MK-801 receptor binding site of the NMDA receptor-ionophore complex.
Pharmacodynamics/Kinetics
Absorption: Rapid and almost complete; food has no effect upon the tablet's absorption
Distribution: Vd: 0.7-0.8 L/kg
Protein binding: 22% to 25%, primarily to albumin
Half-life elimination: 20-23 hours (average); prolonged in renal dysfunction
Time to peak, serum: 3-5 hours
Excretion: Urine (40% to 50% as unchanged drug, 40% as inactive metabolites)
Dosage
Anticonvulsant:
Monotherapy: Children >14 years and Adults:
Initial: 1200 mg/day in divided doses 3 or 4 times/day; titrate previously untreated patients under close clinical supervision, increasing the dosage in 600 mg increments every 2 weeks to 2400 mg/day based on clinical response and thereafter to 3600 mg/day as clinically indicated
Conversion to monotherapy: Initiate at 1200 mg/day in divided doses 3 or 4 times/day, reduce the dosage of the concomitant anticonvulsant(s) by 20% to 33% at the initiation of felbamate therapy; at week 2, increase the felbamate dosage to 2400 mg/day while reducing the dosage of the other anticonvulsant(s) up to an additional 33% of their original dosage; at week 3, increase the felbamate dosage up to 3600 mg/day and continue to reduce the dosage of the other anticonvulsant(s) as clinically indicated
Adjunctive therapy: Note: Dose of concomitant carbamazepine, phenobarbital, phenytoin, or valproic acid should be decreased by 20% to 33% when initiating felbamate therapy. Further dosage reductions may be necessary as dose of felbamate is increased.
Children 2-14 years with Lennox-Gastaut syndrome: Initial: 15 mg/kg/day in divided doses 3 or 4 times/day; may increase once per week by 15 mg/kg/day increments up to 45 mg/kg/day in divided doses 3 or 4 times/day.
Children >14 years and Adults: Initial: 1200 mg/day in divided doses 3 or 4 times/day; may increase once per week by 1200 mg/day increments up to 3600 mg/day in divided doses 3 or 4 times/day.
Dosage adjustment in renal impairment: Use caution; reduce initial and maintenance doses by 50% (half-life prolonged by 9-15 hours)
Administration: Oral
Administer on an empty stomach for best absorption.
Monitoring Parameters
Monitor serum levels of concomitant anticonvulsant therapy; obtain transaminases (AST, ALT) levels before initiation of therapy and periodically thereafter and bilirubin weekly. Hematologic evaluations before therapy begins, frequently during therapy, and for a significant period after discontinuation. Monitor for suicidality (eg, suicidal thoughts, depression, behavioral changes).
Reference Range
Not necessary to routinely monitor serum drug levels, since dose should be titrated to clinical response
Dietary Considerations
May be taken without regard to meals.
Patient Education
While using this medication, do not use alcohol. Maintain adequate hydration, unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, blurred vision, fever (especially in children), insomnia, fatigue, nervousness, nausea, vomiting, loss of appetite, or dry mouth. Wear identification of epileptic status and medications. Report CNS changes, mentation changes, suicide ideation, or changes in cognition; muscle cramping, weakness, tremors, changes in gait; persistent GI symptoms (cramping, constipation, vomiting, anorexia); rash or skin irritations; unusual bruising or bleeding (mouth, urine, stool); cough, runny nose, sore throat, or respiratory difficulty; or worsening of seizure activity or loss of seizure control.
Geriatric Considerations
Clinical studies have not included large numbers of patients >65 years of age. Due to decreased hepatic and renal function, dosing should start at the lower end of the dosage range.
Additional Information
Monotherapy has not been associated with gingival hyperplasia, impaired concentration, weight gain, or abnormal thinking. Because felbamate is the only drug shown effective in Lennox-Gastaut syndrome, it is considered an orphan drug for this indication.
Anesthesia and Critical Care Concerns/Other Considerations
Monotherapy has not been associated with gingival hyperplasia, impaired concentration, weight gain, or abnormal thinking. Because felbamate is the only drug shown effective in Lennox-Gastaut syndrome, it is considered an orphan drug.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation) and abnormal taste.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Anxiety and dizziness are common; may cause drowsiness, insomnia, or depression
Mental Health: Effects on Psychiatric Treatment
Carbamazepine may decrease effects of felbamate; may increase effects of valproic acid
Nursing: Physical Assessment/Monitoring
Monitor therapeutic effectiveness (seizure activity, force, type, duration) at beginning of therapy and periodically throughout. Taper dosage slowly when discontinuing. Teach patient safety and seizure precautions.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension, oral: 600 mg/5 mL (240 mL, 473 mL)
Felbatol®: 600 mg/5 mL (240 mL, 960 mL)
Tablet, oral: 400 mg, 600 mg
Felbatol®: 400 mg, 600 mg [scored]
Pricing: U.S. (www.drugstore.com)
Suspension (Felbatol)
600 mg/5 mL (237): $590.01
Tablets (Felbatol)
400 mg (90): $429.97
600 mg (90): $500.02
References
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,” Epilepsia, 1999, 40(6):803-8.
Kaufmann DW, Kelly JP, Anderson T, et al, “Evaluation of Case Reports of Aplastic Anemia Among Patients Treated With Felbamate,” Epilepsia, 1997, 38(12):1265-9.
Pellock JM, “Felbamate in Epilepsy Therapy: Evaluating the Risks,” Drug Saf, 1999, 21(3):225-39.
Perucca E, “Clinically Relevant Drug Interaction With Antiepileptic Drugs,” Br J Clin Pharmacol, 2005, 61(3):246-55.
International Brand Names
Lexi-Comp.com
Last full review/revision January 2012
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