Felbamate

Pronunciation: fel-BAM-ate
Class: Anticonvulsant

Trade Names

Felbatol
- Tablets, oral 400 mg
- Tablets, oral 600 mg
- Suspension, oral 600 mg per 5 mL

Pharmacology

May reduce seizure spread in generalized tonic-clonic or partial seizures and may increase seizure threshold in absence seizures.

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Pharmacokinetics

Distribution

Vd is approximately 756 mL/kg. 22% to 25% bound to plasma proteins.

Metabolism

Approximately 40% is unidentified metabolites and conjugates and approximately 15% is parahydroxyfelbamate, 2-hydroxyfelbamate, and felbamate monocarbamate; none have significant anticonvulsant activity.

Elimination

The half-life is 20 to 23 h. Cl is approximately 30 mL/h/kg. Approximately 40% to 50% is excreted unchanged in the urine.

Special Populations

Renal Function Impairment

Decreased felbamate Cl (40% to 50%) and increased half-life (9 to 15 h prolongation) were associated with diminishing renal function.

Gender

Plasma concentrations in males and females were similar.

Race

Pharmacokinetics of felbamate have not been evaluated.

Indications and Usage

Monotherapy or adjunctive therapy in treatment of partial seizures with and without generalization in epileptic adults. Adjunctive therapy in treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children.

Contraindications

Hypersensitivity to felbamate or ingredients of this product; hypersensitivity reactions to other carbamates; history of any blood dyscrasia or hepatic dysfunction.

Dosage and Administration

Initial Monotherapy
Adults and Adolescents 14 y and older

PO 1,200 mg/day in 3 or 4 divided doses; increase in 600 mg increments every 2 wk to 2,400 mg/day and then 3,600 mg/day if indicated.

Conversion to Monotherapy
Adults and Adolescents 14 y and older Initial dose

PO 1,200 mg/day in 3 or 4 divided doses, reducing dose of other antiepileptic drugs by one-third. At week 2, increase felbamate to 2,400 mg/day, and at week 3, increase to 3,600 mg/day; continue to reduce dose of other antiepileptic drugs as indicated.

Adjunctive Therapy
Adults and adolescents 14 y and older

PO 1,200 mg/day in 3 or 4 divided doses; reduce original dose of other antiepileptic drugs by 20% for 1 wk. At week 2, increase felbamate to 2,400 mg/day, and at week 3, increase to 3,600 mg/day if needed; reduce dosage of other antiepileptic drugs as clinically indicated.

Children 2 to 14 y of age with Lennox-Gastaut Syndrome

PO 15 mg/kg/day in 3 or 4 divided doses while reducing other antiepileptic drugs by 20%. Increase felbamate by 15 mg/kg/day increments at weekly intervals up to 45 mg/kg/day; continue to reduce dosage of other antiepileptic drugs as needed.

Renal Function Impairment

PO Reduce starting and maintenance doses by one-half. Adjunctive therapy with medications that affect felbamate plasma concentrations, especially antiepileptic drugs (AEDs), may warrant further reductions in felbamate daily doses in patients with renal dysfunction.

General Advice

  • Reduce the dosage of other AEDs by 20% to 33% to minimize adverse effects.
  • Instruct patient to take tablet whole with full glass of water, and to not crush or chew.
  • May administer tablet with food.
  • Administer suspension if patient is unable to swallow tablets.
  • Shake suspension prior to administration.

Storage/Stability

Store between 68° and 77°F.

Drug Interactions

Antiepileptic drugs (ie, carbamazepine, phenytoin, phenobarbital, valproate)

Concurrent use of felbamate with certain antiepileptic drugs may decrease felbamate concentrations and increase the concentration of the other antiepileptic. Valproate did not alter the pharmacokinetics of felbamate. Dosage adjustments are required.

Cabazitaxel

Felbamate may decrease the plasma concentrations of cabazitaxel. Avoid concurrent use.

Contraceptives, hormonal

Contraceptive effectiveness may be decreased when coadministered with felbamate. An alternative form of birth control may be advisable.

QT interval–prolonging drugs (eg, antiarrhythmic agents [eg, amiodarone, bretylium, disopyramide, dofetilide, procainamide, propafenone, quinidine, sotalol], arsenic trioxide, chlorpromazine, cisapride, dolasetron, dasatinib, droperidol, haloperidol, lapatinib, mefloquine, mesoridazine, methadone, moxifloxacin, nilotinib, pentamidine, pimozide, romidepsin, tacrolimus, thioridazine, vandetanib, and ziprasidone)

The risk of life-threatening cardiac arrhythmias, including torsades de pointes, may be increased. Felbamate should not be taken with any other drug that prolongs the QT interval.

Ulipristal

Felbamate may decrease the plasma concentrations of ulipristal. Monitor closely.

Warfarin

The effects of warfarin may be increased. Monitor closely and adjust warfarin dosage as needed.

Adverse Reactions

Cardiovascular

Chest pain (3%); palpitations, tachycardia (at least 1%); atrial arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, cardiac failure, cerebrovascular disorder, flushing, Henoch-Schönlein purpura (vasculitis), hypertension, hypotension, ischemic necrosis, thrombophlebitis, torsades de pointes (postmarketing).

CNS

Somnolence (48%); headache (37%); dizziness, insomnia (18%); fatigue (17%); abnormal gait (10%); ataxia, emotional lability, nervousness, thinking abnormalities (7%); tremor (6%); anxiety, depression (5%); paresthesia (4%); stupor (3%); aggressive reaction, agitation, asthenia, malaise, psychological disturbance (at least 1%); cerebral edema, choreoathetosis, coma, confusion, delusion, dyskinesia, encephalopathy, extrapyramidal disorder, manic reaction, mononeuritis, paralysis, paranoid reactions, psychosis, status epilepticus (postmarketing).

Dermatologic

Rash (10%); acne (3%); pruritus (at least 1%); abnormal body odor, alopecia, lichen planus, livedo reticularis, sweating, TEN (postmarketing).

EENT

Otitis media, pharyngitis (10%); miosis, rhinitis (7%); diplopia, taste perversion (6%); abnormal vision (5%); sinusitis (4%); conjunctivitis, decreased hearing, hemianopsia (postmarketing).

GI

anorexia (55%); vomiting (39%); nausea (34%); constipation (13%); dyspepsia (12%); abdominal pain, diarrhea (5%); dry mouth (3%); acquired megacolon, dysphagia, enteritis, gastric ulcer, gastritis, glossitis, gastric dilation, gastroesophageal reflux, GI hemorrhage, gingival bleeding, ileus, intestinal obstruction, pancreatitis, rectal hemorrhage, ulcerative stomatitis (postmarketing).

Genitourinary

Intramenstrual bleeding, UTI (3%); abnormal renal function, acute renal failure, dysuria, hematuria, hepatorenal syndrome, menstrual disorder, nephrosis, placental disorder, urinary retention, vaginal hemorrhage (postmarketing).

Hematologic

Purpura (13%); leukopenia (7%); anemia, aplastic anemia, coagulation disorders, DIC, hematemesis, hemolytic anemia, hemolytic uremic syndrome, hypochromic anemia, limb embolism, mean corpuscular volume increased with and without anemia, pancytopenia, prothrombin time increased and decreased (postmarketing).

Hepatic

Increased ALT (5%); increased AST (at least 1%); hepatic failure, hepatitis, jaundice.

Metabolic-Nutritional

Weight decrease (7%); hypophosphatemia (3%); weight increase (at least 1%); dehydration, edema, hyperammonemia, hyperglycemia, hypernatremia, hypocalcemia, hypoglycemia, hypomagnesemia, SIADH (postmarketing).

Musculoskeletal

Arthralgia, involuntary muscle contraction, muscle weakness, rhabdomyolysis, rigors (postmarketing).

Respiratory

Upper respiratory tract infection (45%); coughing (7%); asthma, dyspnea, epistaxis, hypoxia, pleural effusion, pneumonia, pneumonitis, respiratory depression, respiratory insufficiency, pulmonary hemorrhage (postmarketing).

Miscellaneous

Fever (23%); hiccup (10%); pain (7%); facial edema, myalgia (3%); influenza-like symptoms (at least 1%); gangrene, hypothermia, hyperpyrexia, lupus erythematous syndrome, leukemia including myelogenous leukemia and lymphoma (T-cell and B-cell lymphoproliferative disorders), neoplasm, peripheral ischemia, sepsis, sudden infant death syndrome, sudden death (postmarketing).

Fetal disorders

Anencephaly, encephalocele, fetal death, genital malformation, microcephaly (postmarketing).

Precautions

Warnings

Aplastic anemia

Use is associated with a marked increase in the incidence of aplastic anemia and should only be used in patients whose epilepsy is so severe that the risk of aplastic anemia is deemed acceptable in light of the benefits conferred by its use. Aplastic anemia occurs at an incidence that may be more than a 100-fold greater than that seen in the untreated population. The risk of death in patients with aplastic anemia generally varies; current estimates of the overall case fatality rate are in the range of 20% to 30%, but rates as high as 70% have been reported in the past. Clinical manifestation of aplastic anemia may not be seen until after a patient has been on felbamate for several months. Aplastic anemia typically develops without premonitory clinical or laboratory signs, the full-blown syndrome presenting with signs of infection, bleeding, or anemia. Discontinue felbamate if any evidence of bone marrow depression occurs. Accordingly, patients who are discontinued from felbamate remain at risk for developing anemia for a variable, and unknown, period afterward.

Hepatic failure

Acute liver failure is associated with the use of felbamate. The reported rate in the United States has been approximately 6 cases of liver failure leading to death or transplant per 75,000 patient-years of use. Of the cases reported, approximately 67% resulted in death or liver transplantation, usually within 5 weeks of the onset of signs and symptoms of liver failure. Felbamate should not be prescribed for anyone with a history of hepatic dysfunction. Treatment with felbamate should be initiated only in individuals without active liver disease and with normal baseline serum transaminases. Monitoring of serum transaminase levels (AST and ALT) is recommended at baseline and periodically thereafter. Discontinue if serum AST or ALT levels become increased at least 2 times the ULN, or if clinical signs and symptoms suggest liver failure.


Monitor

Monitor for effectiveness; note any changes in seizure patterns and frequency. Perform full hematologic evaluations prior to initiating felbamate and frequently during therapy and for a significant period of time after discontinuation of therapy. Monitor serum transaminase levels (AST and ALT) at baseline and periodically thereafter. Monitor patients for emergence or worsening of depression, unusual changes in mood or behavior, or the emergence of suicidal thoughts or behavior, or thoughts of self-harm.


Pregnancy

Category C .

Lactation

Excreted in breast milk. Because of potential for serious toxicity (eg, aplastic anemia, acute liver failure) in breast-feeding infants, felbamate should probably not be used during breast-feeding.

Children

Safety and efficacy not established other than for adjunctive therapy of Lennox-Gastaut syndrome.

Elderly

Use caution and start with low doses.

Renal Function

Use with caution in patients with renal dysfunction. Reduced doses are required.

Hepatic Function

Contraindicated in patients with a history of hepatic dysfunction.

Carcinogenesis

Drug may have carcinogenic potential.

Discontinuation

Withdraw drug slowly to avoid increased seizure frequency.

Suicidal behavior and ideation

AEDs, including felbamate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Increased risk has been observed as early as 1 week after starting treatment with AEDs.

Overdosage

Symptoms

Mild gastric distress and a resting heart rate of 100 bpm.

Patient Information

  • Inform patients that their health care provider should obtain written, informed consent prior to initiation of felbamate therapy.
  • Inform patients to take tablet whole; do not crush. Tablet may be taken with food.
  • Caution patients to not stop taking this medication suddenly because of possibility of increasing seizure frequency.
  • Inform patients that felbamate use has been associated with aplastic anemia and to report any signs of infection, bleeding, easy bruising, or signs of anemia such as fatigue, weakness, or lassitude immediately. Inform patient that this adverse effect may occur even after the medication has been discontinued.
  • Inform patients that felbamate use has been associated with hepatic failure and discuss the importance of liver function testing before starting felbamate and frequently after starting treatment. Inform patients of signs and symptoms of liver dysfunction such as jaundice, anorexia, GI complaints, and malaise and to report these immediately should they occur.
  • Counsel patients, their families, and their caregivers that AEDs, including felbamate, may increase the risk of suicidal thoughts and behavior, and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts or behaviors, or thoughts of self-harm. Instruct patients to immediately report behaviors of concern to their health care provider.
  • Advise patient that felbamate may cause drowsiness, dizziness, and vision problems, and to use caution while driving or performing other tasks requiring mental alertness. Advise patient not to drink alcohol or take other medications that may cause drowsiness and dizziness until the patient has consulted with a health care provider.
  • Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of AEDs during pregnancy. To enroll, patients can call 1-888-233-2334.

Copyright © 2009 Wolters Kluwer Health.

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