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Felbamate

Pronunciation

(FEL ba mate)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

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Suspension, Oral:

Felbatol: 600 mg/5 mL (237 mL, 946 mL)

Generic: 600 mg/5 mL (237 mL, 240 mL, 473 mL, 946 mL)

Tablet, Oral:

Felbatol: 400 mg, 600 mg [scored]

Generic: 400 mg, 600 mg

Brand Names: U.S.

  • Felbatol

Pharmacologic Category

  • Anticonvulsant, Miscellaneous

Pharmacology

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.

Absorption

Rapid and almost complete; food has no effect upon the tablet's absorption

Distribution

Vd: 0.7 to 0.8 L/kg

Excretion

Urine (40% to 50% as unchanged drug, 40% as inactive metabolites)

Clearance: Decreased by 40% to 50% in patients with renal impairment

Time to Peak

Serum: 3 to 5 hours

Half-Life Elimination

20 to 23 hours (average); prolonged by 9 to 15 hours in patients with renal impairment

Protein Binding

22% to 25%, primarily to albumin

Use: Labeled Indications

Monotherapy or adjunctive therapy in the treatment of partial seizures (with and without generalization); adjunctive therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome; not indicated for use as first-line treatment

Contraindications

Hypersensitivity to felbamate or any component of the formulation; known sensitivity to other carbamates; history of any blood dyscrasia or hepatic dysfunction

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 if 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 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% 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; 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; 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%.

Dosage adjustment in hepatic impairment: Use is contraindicated.

Administration

May be administered with or without food. Shake suspension prior to use.

Dietary Considerations

May be taken without regard to meals.

Storage

Store in tightly closed container at controlled room temperature of 20°C to 25°C (68°F to 77°F).

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Barbiturates: Felbamate may increase the serum concentration of Barbiturates. Barbiturates may decrease the serum concentration of Felbamate. 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. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. 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. 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. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosphenytoin: May decrease the serum concentration of Felbamate. Felbamate may increase the serum concentration of Fosphenytoin. 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. Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Hydrocodone: CNS Depressants may enhance the CNS depressant effect of Hydrocodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. 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. 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. Consider therapy modification

Metyrosine: CNS Depressants may enhance the sedative effect of Metyrosine. Monitor therapy

Mianserin: May diminish the therapeutic effect of Anticonvulsants. Monitor therapy

Mifepristone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mifepristone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Orlistat: May decrease the serum concentration of Anticonvulsants. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

PHENobarbital: May decrease the serum concentration of Felbamate. Felbamate may increase the serum concentration of PHENobarbital. 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. 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. Consider therapy modification

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

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. Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. 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. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Ulipristal: Felbamate may decrease the serum concentration of Ulipristal. Avoid combination

Valproate Products: Felbamate may increase the serum concentration of Valproate Products. Consider therapy modification

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

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 (children 16%; adults 7%)

Dermatologic: Purpura (children 13%)

Gastrointestinal: Anorexia (children 55%; adults 19%), vomiting (children 39%; adults 9% to 17%), nausea (children 7%; adults 34%), dyspepsia (9% to 12%), constipation (7% to 11%)

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: Abnormal thinking (children 7%), ataxia (children 7%; adults 4%), emotional lability (children 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 (children 7%; adults 3%), 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 (children 7%; adults ≤1%), granulocytopenia (≤1%), leukocytosis (≤1%), lymphadenopathy (≤1%), thrombocytopenia (≤1%)

Hepatic: Liver function tests increased (1% to 5%), 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 (children 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%), LDH increased (≤1%)

<1% (Limited to important or life-threatening): Acute renal failure, agranulocytosis, allergic reaction, alopecia, anaphylactoid reaction, anemia, aplastic anemia, atrial arrhythmia, atrial fibrillation, bradycardia, 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, flushing, gastric ulcer, gastritis, gastroesophageal reflux, GI hemorrhage, gingival bleeding, glossitis, hematemesis, hematuria, hemolytic anemia, Henoch-Schönlein vasculitis, hepatic failure, hepatitis, hepatorenal syndrome, hyperammonemia, hyper-/hypoglycemia, hyper-/hypotension, hypernatremia, hypocalcemia, hypomagnesemia, hypoxia, ileus, ischemic necrosis, jaundice, 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, status epilepticus, Stevens-Johnson syndrome, sudden death, suicidal behavior/ideation, SVT, thrombophlebitis, torsade de pointes, toxic epidermal necrolysis, ulcerative stomatitis, urinary retention, urticaria

ALERT: U.S. Boxed Warning

Aplastic anemia:

The use of felbamate is associated with a marked increase in the incidence of aplastic anemia. Accordingly, felbamate 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. Ordinarily, a patient should not be placed on and/or continued on felbamate without consideration of appropriate expert hematologic consultation.

Among felbamate-treated patients, aplastic anemia (pancytopenia in the presence of a bone marrow largely depleted of hematopoietic precursors) occurs at an incidence that may be more than a 100-fold greater than that seen in the untreated population (ie, 2 to 5 per million persons per year). The risk of death in patients with aplastic anemia generally varies as a function of its severity and etiology; 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.

There are too few felbamate-associated cases, and too little known about them to provide a reliable estimate of the syndrome's incidence or its case fatality rate or to identify the factors, if any, that might conceivably be used to predict who is at greater or lesser risk.

In managing patients on felbamate, the clinical manifestation of aplastic anemia may not be seen until after a patient has been taking felbamate for several months (eg, onset of aplastic anemia among felbamate-exposed patients for whom data are available has ranged from 5 to 30 weeks). However, the injury to bone marrow stem cells that is held to be ultimately responsible for the anemia may occur weeks to months earlier. Accordingly, patients who are discontinued from felbamate remain at risk for developing anemia for a variable, and unknown, period afterwards.

It is not known whether the risk of developing aplastic anemia changes with duration of exposure. Consequently, it is not safe to assume that a patient who has been on felbamate without signs of hematologic abnormality for long periods of time is without risk.

It is not known whether the dose of felbamate affects the incidence of aplastic anemia.

It is not known whether concomitant use of antiepileptic drugs (AEDs) and/or other drugs affects the incidence of aplastic anemia.

Aplastic anemia typically develops without premonitory clinical or laboratory signs; the full blown syndrome presents with signs of infection, bleeding, or anemia. Accordingly, routine blood testing cannot be reliably used to reduce the incidence of aplastic anemia, but, it will, in some cases, allow the detection of the hematologic changes before the syndrome declares itself clinically. Discontinue felbamate if any evidence of bone marrow depression occurs.

Hepatic failure:

Evaluation of postmarketing experience suggests that 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. This rate is an underestimate because of underreporting, and the true rate could be considerably greater than this. For example, if the reporting rate is 10%, the true rate would be 1 case per 1,250 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. The earliest onset of severe hepatic dysfunction followed subsequently by liver failure was 3 weeks after initiation of felbamate. Although some reports described dark urine and nonspecific prodromal symptoms (eg, anorexia, malaise, GI symptoms), in other reports it was not clear if any prodromal symptoms preceded the onset of jaundice.

It is not known whether the risk of developing hepatic failure changes with duration of exposure.

It is not known whether the dosage of felbamate affects the incidence of hepatic failure.

It is not known whether concomitant use of other AEDs and/or other drugs affects the incidence of hepatic 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. It has not been proved that periodic serum transaminase testing will prevent serious injury, but it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery. There is no information available that documents how rapidly patients can progress from normal liver function to liver failure, but other drugs known to be hepatotoxins can cause liver failure rapidly (eg, from normal enzymes to liver failure in 2 to 4 weeks). Accordingly, monitoring of serum transaminase levels (AST and ALT) is recommended at baseline and periodically thereafter. While more frequent monitoring increases the chances of early detection, the precise schedule for monitoring is a matter of clinical judgment.

Discontinue felbamate if serum AST or serum ALT levels become increased at least 2 times the upper limit of normal, or if clinical signs and symptoms suggest liver failure. Patients who develop evidence of hepatocellular injury while taking felbamate and are withdrawn from the drug for any reason should be presumed to be at increased risk for liver injury if felbamate is reintroduced. Accordingly, such patients should not be considered for re-treatment.

Warnings/Precautions

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 patients with renal impairment; half-life may be increased.

Concurrent drug therapy issues:

• Sedatives: CNS effects may be potentiated when used with other sedative drugs or ethanol.

Other warnings/precautions:

• Appropriate use: Not indicated for use as a first-line antiepileptic treatment; only recommended 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.

• 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.

Monitoring Parameters

Monitor serum levels of concomitant anticonvulsant therapy; obtain transaminases (AST, ALT) levels before initiation of therapy and periodically thereafter. Hematologic evaluations before therapy begins, frequently during therapy, and for a significant period after discontinuation. Monitor for suicidality (eg, suicidal thoughts, depression, behavioral changes).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. 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 North American Antiepileptic Drug (AED) Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, fatigue, headache, nausea, vomiting, lack of appetite, constipation, insomnia, diarrhea, rhinorrhea, pharyngitis, tremors, abdominal pain, change in taste, weight loss, or hiccups. Have patient report immediately to prescriber signs of infection, signs of aplastic anemia (fever, pharyngitis, mouth sores, infections, bruising, or purple skin splotches), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), illogical thinking, change in balance, bruising, bleeding, vision changes, angina, tachycardia, arrhythmia, muscle pain, loss of strength and energy, suicidal ideation, depression, anxiety, agitation, irritability, panic attacks, or mood changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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