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  • CLASSES

    Anticonvulsants, Carbamates

    BOXED WARNING

    Hepatic disease, hepatitis, hepatotoxicity, jaundice

    Felbamate may cause hepatotoxicity and hepatic failure. Felbamate is contraindicated in patients with current or previous hepatic disease or dysfunction (e.g., hepatitis). In September 1994, the manufacturer issued a letter stating 8 cases of acute hepatic failure, including 4 deaths, were associated with the use of felbamate. It is thought that hepatic failure in felbamate-treated patients greatly exceeds that which occurs in the general population. Therefore, it is recommended that felbamate only be used in patients with severe epilepsy for which the benefits of the drug outweigh the risks of hepatic failure and other toxicities. Whether pre-existing hepatic disease increases the risk of felbamate-induced hepatotoxicity is unknown. It is not known if other risk factors exist, such as dose, concurrent use of other medications, or length of therapy. Therefore, all patients receiving felbamate should be monitored for signs of hepatotoxicity. Monitoring should include baseline liver function tests (i.e., ALT, AST, bilirubin), and periodically thereafter. While frequent monitoring of liver function tests may increase the likelihood of early detection, the precise schedule for monitoring is a matter of clinical judgement. Patients should be advised to be alert for signs of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they should occur. Felbamate should be discontinued if either serum AST or ALT levels become increased 2 or more times the upper limit of normal (ULN), or if clinical signs and symptoms suggest liver failure. Any patient withdrawn from the drug for liver injury are considered at increased risk for such problems if the drug is re-introduced. Do not restart felbamate in these patients.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral anticonvulsant agent chemically similar to meprobamate, but does not possess muscle-relaxant activity. Used for partial seizures in adults and Lennox-Gastaut syndrome in children and adults. Aplastic anemia and acute hepatic failure limit use to seizures refractory to other agents; close monitoring for emerging or worsening suicidal thoughts/behavior or depression is recommended.

    COMMON BRAND NAMES

    Felbatol

    HOW SUPPLIED

    Felbamate/Felbatol Oral Susp: 5mL, 600mg
    Felbamate/Felbatol Oral Tab: 400mg, 600mg

    DOSAGE & INDICATIONS

    For the treatment of partial seizures with or without generalization in adults.
    NOTE: Felbamate has not been systematically studied as initial monotherapy.
    Oral dosage-Monotherapy
    Adults and Adolescents > 14 years

    1200 mg/day PO in 3—4 divided doses. Increase dose in 600 mg increments every 2 weeks to 2400 mg/day PO based on clinical response. Doses may be increased to 3600 mg/day PO if clinically indicated. Previously untreated patients should be titrated under close clinical supervision.

    Oral dosage-Conversion to Monotherapy
    Adults and Adolescents > 14 years

    Initiate at 1200 mg/day PO in 3—4 divided doses. Upon initiation of felbamate therapy, reduce the dosage of other antiepileptic drugs (AEDs) by one-third (1/3). At week 2, increase felbamate dose to 2400 mg/day PO while decreasing the other AEDs dose by an additional one-third of the original dose. At week 3, increase the dose of felbamate to 3600 mg/day PO given in divided doses and continue to reduce the dose of the other AEDs as clinically indicated.

    Oral dosage-Adjunctive Therapy
    Adults and Adolescents > 14 years

    Add felbamate at 1200 mg/day PO in 3—4 divided doses and reduce the dose of other AEDs by 20—30%. The dosage reduction of other AEDs will help maintain plasma concentrations and reduce side effects of concurrent phenytoin, valproic acid, or carbamazepine and its metabolites. Serum concentrations of other anticonvulsants should be obtained and dosage adjustments made as necessary. Increase felbamate dosage by 1200 mg/day increments at weekly intervals to a maximum of 3600 mg/day PO given in divided doses.

    For the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children.
    Oral dosage-Adjunctive Therapy
    Adolescents and Children 2 - 14 years

    Add felbamate at 15 mg/kg/day PO in 3—4 divided doses while reducing doses of other AEDs by 20—30%. The dosage reduction of other AEDs will help maintain plasma concentrations and reduce side effects of concurrent phenytoin, valproic acid, or carbamazepine and its metabolites. Serum concentrations of other anticonvulsants should be obtained and dosage adjustments made as necessary. Increase felbamate dosage by 15 mg/kg/day increments at weekly intervals to 45 mg/kg/day PO. Maximum dosage is 3600 mg/day.

    MAXIMUM DOSAGE

    Adults

    3600 mg/day PO.

    Elderly

    3600 mg/day PO.

    Adolescents

    3600 mg/day PO.

    Children

    >= 2 years: 3600 mg/day PO.
    < 2 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    The manufacturer advises to avoid use of felbamate in patients with pre-existing hepatic disease.

    Renal Impairment

    In the renally-impaired, starting and maintenance doses should be reduced by 50% (manufacturers recommendation).

    ADMINISTRATION

    NOTE: Felbamate should only be initiated or continued in the management of seizures when, in the physician's opinion, the patient's seizure disorder is refractory to alternative safer anticonvulsant therapy and is so severe that the benefit from therapy outweighs the risk of acute hepatic failure and aplastic anemia. 
     
    For storage information, see specific product information within the How Supplied section.
     
    A MedGuide will be available that discusses the risk of suicidal thoughts and behaviors associated with the use of anticonvulsant medications.

    Oral Administration

    Felbamate is administered orally.

    Oral Solid Formulations

    Tablets may be administered without regard to meals.

    Oral Liquid Formulations

    Shake the oral suspension well before using.
    The effect of food on GI absorption from the oral suspension has not been evaluated.

    STORAGE

    Felbatol:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Carbamate hypersensitivity

    Felbamate is contraindicated in patients with a felbamate or carbamate hypersensitivity. Patients sensitive to carbamate derivatives (e.g., meprobamate, carisoprodol) may also be sensitive to felbamate.

    Agranulocytosis, anemia, bone marrow suppression, hematological disease, leukopenia, neutropenia, thrombocytopenia

    The use of felbamate is associated with a marked increase in the incidence of aplastic anemia (pancytopenia in the presence of a bone marrow largely depleted of hematologic precursor cells). Felbamate should only be used in patients with epilepsy that is so severe that the risk of aplastic anemia is acceptable in accordance with the benefits associated with felbamate use. A hematologic consultation is recommended to determine appropriateness of use prior to treatment. Among felbamate-treated patients, aplastic anemia occurs at an incidence that may be more than 100-fold greater than that seen in the untreated population (e.g., 2 to 5 cases per million persons per year). Cases of aplastic anemia may be fatal and fatalities are dependent on the severity and etiology of the presentation, but typically are in the range of 20 to 30%, and may be as high as 70%. Too little is known about felbamate-induced aplastic anemia to determine fatality percentages or which patients are more at risk for this serious adverse reaction. Clinical manifestations may not be present for several months after therapy is initiated; where data are available the onset has ranged from 5 TO 30 weeks following the start of therapy. Bone marrow stem cell changes may occur weeks to months earlier than clinical presentation. Patients who are discontinued off the drug therefore remain at risk for aplastic anemia for an unknown time after drug discontinuation. It is not known if the duration of felbamate exposure or the dose used influences the risk for aplastic anemia. It is also not known if concurrent therapies may influence this risk. Clinical signs and symptoms may include infection, bleeding or anemia. Routine laboratory testing of the blood cannot be reliably used to reduce the incidence of aplastic anemia. Felbamate is contraindicated in patients with a history of any hematological disease (e.g., leukopenia, neutropenia, agranulocytosis, bone marrow suppression, thrombocytopenia, anemia, aplastic anemia, or other hematological disease because of the potential increased risk of hematologic toxicity. A baseline CBC with platelets and reticulocytes should be obtained, as well as routine laboratory monitoring throughout treatment. Felbamate should be discontinued if signs and symptoms of hematologic abnormalities or any sign of bone marrow depression occurs. Patients who are discontinued from felbamate remain at risk for developing anemia for an uncertain length of time.

    Hepatic disease, hepatitis, hepatotoxicity, jaundice

    Felbamate may cause hepatotoxicity and hepatic failure. Felbamate is contraindicated in patients with current or previous hepatic disease or dysfunction (e.g., hepatitis). In September 1994, the manufacturer issued a letter stating 8 cases of acute hepatic failure, including 4 deaths, were associated with the use of felbamate. It is thought that hepatic failure in felbamate-treated patients greatly exceeds that which occurs in the general population. Therefore, it is recommended that felbamate only be used in patients with severe epilepsy for which the benefits of the drug outweigh the risks of hepatic failure and other toxicities. Whether pre-existing hepatic disease increases the risk of felbamate-induced hepatotoxicity is unknown. It is not known if other risk factors exist, such as dose, concurrent use of other medications, or length of therapy. Therefore, all patients receiving felbamate should be monitored for signs of hepatotoxicity. Monitoring should include baseline liver function tests (i.e., ALT, AST, bilirubin), and periodically thereafter. While frequent monitoring of liver function tests may increase the likelihood of early detection, the precise schedule for monitoring is a matter of clinical judgement. Patients should be advised to be alert for signs of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they should occur. Felbamate should be discontinued if either serum AST or ALT levels become increased 2 or more times the upper limit of normal (ULN), or if clinical signs and symptoms suggest liver failure. Any patient withdrawn from the drug for liver injury are considered at increased risk for such problems if the drug is re-introduced. Do not restart felbamate in these patients.

    Renal failure, renal impairment

    Use felbamate with caution in patients with pre-existing renal impairment, particularly renal failure. The half-life of the drug is prolonged and clearance reduced. Dosage adjustments are recommended.

    Depression, suicidal ideation

    In January 2008, the FDA alerted healthcare professionals of an increased risk of suicidal ideation and behavior in patients receiving anticonvulsants to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). This alert followed an initial request by the FDA in March 2005 for manufacturers of marketed anticonvulsants to provide data from existing controlled clinical trials for analysis. Prior to this request, preliminary evidence had suggested a possible link between anticonvulsant use and suicidality. The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (>= 5 years of age). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%), corresponding to an estimated 2.1 per 1000 (95% CI: 0.7—4.2) more patients in the drug treatment groups who experienced suicidal behavior or ideation. The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Data were analyzed from drugs with adequately designed clinical trials including carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. However, this is considered to be a class effect. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening suicidal thoughts/behavior or depression. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Anticonvulsants such as felbamate should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    Pregnancy

    Felbamate is classified as FDA pregnancy risk category C. There are no studies in pregnant women to determine the effect of felbamate on the fetus. It is not teratogenic in animal models. However, in rats, there was a decrease in pup weight and an increase in pup deaths during the post-birth lactation period; the cause for these deaths is not known. In addition, as a result of the synthesis process, felbamate could contain small amounts of two known animal carcinogens, the genotoxic compound ethyl carbamate (urethane) and the non-genotoxic compound methyl carbamate. The serious toxicities of felbamate, such as aplastic anemia, would also warrant that felbamate be used during pregnancy only if clearly needed. The effect of felbamate on labor and delivery in humans is unknown. Physicians are advised to recommend that pregnant patients receiving felbamate enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry.

    Breast-feeding

    According to the manufacturer, felbamate is excreted into breast milk, but its effects on the infant are unknown. In rats, there was a decrease in pup weight and an increase in pup deaths during lactation; the reason for the deaths is not determined. Because of the serious toxicities associated with the drug, including aplastic anemia and hepatic failure, breast-feeding should generally be avoided during treatment with felbamate. Consider the benefits of breast-feeding, the risk of potential drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants

    The safety and efficacy of felbamate in children, other than those with Lennox-Gastaut syndrome, have not been studied. The drug is not recommended for children under the age of 2 years or in infants.

    Abrupt discontinuation

    Abrupt discontinuation of felbamate can precipitate seizures.

    Geriatric

    No systematic studies of felbamate in geriatric patients have been conducted. Clinical studies did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently to felbamate than younger adults. Other reported clinical experience has not identified differences in responses. In general, dosage selection for geriatric patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. According to the Beers Criteria, anticonvulsants such as felbamate are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, with the exception of treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If felbamate must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, some anticonvulsants may be used to treat disorders other than seizures (e.g., bipolar disorder, schizoaffective disorder, chronic neuropathic pain, migraine prevention). The need for indefinite continuation in treating any condition should be based on confirmation of the condition and its potential cause(s). Determining effectiveness and tolerability through evaluation of symptoms should be used to adjust doses. Therapeutic drug monitoring is not required or available for most anticonvulsants. In addition, significant signs and symptoms of toxicity can occur at normal or low serum concentrations, and symptom control for seizures or behavior can occur at subtherapeutic serum concentrations. Obtaining serum medication concentrations may assist in identifying toxicity. High or toxic serum concentrations should become a consideration for dosage adjustments. Anticonvulsants may cause liver dysfunction, blood dyscrasias, and serious skin rashes requiring treatment discontinuation. Anticonvulsants may also cause nausea/vomiting, dizziness, ataxia, somnolence/lethargy, incoordination, blurred or double vision, restlessness, toxic encephalopathy, anorexia, and headaches; these effects can increase the risk for falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / 0.1-1.0
    agranulocytosis / Delayed / 0-0.1
    Stevens-Johnson syndrome / Delayed / 0-0.1
    anaphylactoid reactions / Rapid / 0-0.1
    hematemesis / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    cerebral edema / Early / Incidence not known
    coma / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known
    pleural effusion / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    bradycardia / Rapid / Incidence not known
    heart failure / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    fetal death / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 6.9-6.9
    leukopenia / Delayed / 6.5-6.5
    depression / Delayed / 5.3-5.3
    hyperphosphatemia / Delayed / 3.4-3.4
    hallucinations / Early / 0.1-1.0
    euphoria / Early / 0.1-1.0
    esophagitis / Delayed / 0.1-1.0
    lymphadenopathy / Delayed / 0.1-1.0
    thrombocytopenia / Delayed / 0.1-1.0
    bullous rash / Early / 0.1-1.0
    migraine / Early / 0.1-1.0
    hypokalemia / Delayed / 0.1-1.0
    hyponatremia / Delayed / 0.1-1.0
    hypophosphatemia / Delayed / 0.1-1.0
    dystonic reaction / Delayed / 0.1-1.0
    supraventricular tachycardia (SVT) / Early / 0-0.1
    elevated hepatic enzymes / Delayed / 1.0
    palpitations / Early / 1.0
    sinus tachycardia / Rapid / 1.0
    confusion / Early / Incidence not known
    psychosis / Early / Incidence not known
    mania / Early / Incidence not known
    gastritis / Delayed / Incidence not known
    dysphagia / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    hyperammonemia / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    livedo reticularis / Delayed / Incidence not known
    choreoathetosis / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known
    nystagmus / Delayed / Incidence not known
    ataxia / Delayed / Incidence not known
    dyskinesia / Delayed / Incidence not known
    dysarthria / Delayed / Incidence not known
    respiratory depression / Rapid / Incidence not known
    pneumonitis / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    hypoxia / Early / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    vaginal bleeding / Delayed / Incidence not known
    dysuria / Early / Incidence not known
    urinary retention / Early / Incidence not known
    hematuria / Delayed / Incidence not known
    urinary incontinence / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    hypomagnesemia / Delayed / Incidence not known
    hypernatremia / Delayed / Incidence not known
    hypocalcemia / Delayed / Incidence not known
    dehydration / Delayed / Incidence not known
    myasthenia / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    edema / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known

    Mild

    dyspepsia / Early / 8.6-8.6
    vomiting / Early / 8.6-8.6
    paresthesias / Delayed / 8.6-8.6
    headache / Early / 6.9-6.9
    rhinitis / Early / 6.9-6.9
    fatigue / Early / 6.9-6.9
    anxiety / Delayed / 5.2-5.2
    diarrhea / Early / 5.2-5.2
    weight loss / Delayed / 3.4-3.4
    rash (unspecified) / Early / 3.4-3.4
    acne vulgaris / Delayed / 3.4-3.4
    diplopia / Early / 3.4-3.4
    menstrual irregularity / Delayed / 3.4-3.4
    myalgia / Early / 2.6-2.6
    weight gain / Delayed / 0.1-1.0
    appetite stimulation / Delayed / 0.1-1.0
    leukocytosis / Delayed / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    agitation / Early / 1.0
    pruritus / Rapid / 1.0
    asthenia / Delayed / 1.0
    malaise / Early / 1.0
    paranoia / Early / Incidence not known
    emotional lability / Early / Incidence not known
    nausea / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    gastroesophageal reflux / Delayed / Incidence not known
    xerostomia / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    hiccups / Early / Incidence not known
    flatulence / Early / Incidence not known
    purpura / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    drug-induced body odor / Delayed / Incidence not known
    tremor / Early / Incidence not known
    dizziness / Early / Incidence not known
    insomnia / Early / Incidence not known
    drowsiness / Early / Incidence not known
    cough / Delayed / Incidence not known
    epistaxis / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    sinusitis / Delayed / Incidence not known
    miosis / Early / Incidence not known
    dysgeusia / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    hypothermia / Delayed / Incidence not known
    fever / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Major) Avoid concurrent use of dolutegravir with felbamate, as coadministration may result in decreased dolutegravir plasma concentrations. Felbamate is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
    Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
    Amoxapine: (Moderate) Amoxapine, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Coadministration of felbamate and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Coadministration of felbamate and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
    Amphetamine; Dextroamphetamine Salts: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use dextroamphetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures.
    Aspirin, ASA; Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as felbamate, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
    Aspirin, ASA; Carisoprodol; Codeine: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as felbamate, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
    Atazanavir: (Major) Coadministration of felbamate with atazanavir is not recommended. Plasma concentrations of atazanavir may be reduced if these drugs are administered concurrently, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Felbamate is a CYP3A4 inducer; atazanavir is a substrate of CYP3A4.
    Atazanavir; Cobicistat: (Major) Coadministration of felbamate with atazanavir is not recommended. Plasma concentrations of atazanavir may be reduced if these drugs are administered concurrently, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Felbamate is a CYP3A4 inducer; atazanavir is a substrate of CYP3A4. (Major) Coadministration of felbamate with cobicistat is not recommended. Concurrent use may decrease the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Felbamate is a CYP3A4 inducer, while cobicistat is a substrate of CYP3A4.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Concurrent administration of felbamate and other antiepileptic drugs results in changes in serum concentrations of both felbamate and the antiepileptic drugs. Felbamate increases the steady-state serum concentrations of phenobarbital.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with felbamate is necessary, due to the risk of decreased efficacy of axitinib. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Felbamate is a weak CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer, rifampin, significantly decreased the plasma exposure of axitinib in healthy volunteers. Felbamate is also a CYP2C19 inhibitor, which theoretically could increase exposure to axitinib; however, the effects of felbamate on CYP2C19 are not expected to overcome its effects on CYP3A4, as CYP3A4 is the major route of metabolism for axitinib.
    Bedaquiline: (Major) Avoid concurrent use of felbamate with bedaquiline. Felbamate is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Concurrent administration of felbamate and other antiepileptic drugs results in changes in serum concentrations of both felbamate and the antiepileptic drugs. Felbamate increases the steady-state serum concentrations of phenobarbital.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and felbamate may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; felbamate induces CYP3A4.
    Bupropion: (Major) Bupropion should not be used by patients taking anticonvulsants for seizures because it may decrease the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function.
    Bupropion; Naltrexone: (Major) Bupropion should not be used by patients taking anticonvulsants for seizures because it may decrease the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function.
    Carbamazepine: (Moderate) Concurrent administration of felbamate and other antiepileptic drugs results in changes in serum concentrations of both felbamate and the antiepileptic drugs. Felbamate causes a decrease in the steady-state plasma concentration of carbamazepine but increases concentrations of carbamazepine epoxide, a carbamazepine metabolite.
    Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as felbamate, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
    Citalopram: (Moderate) The plasma concentration of citalopram, a CYP2C19 substrate, may be increased when administered concurrently with felbamate, a CYP2C19 inhibitor. Because citalopram causes dose-dependent QT prolongation, the maximum daily dose should not exceed 20 mg per day in patients receiving CYP2C19 inhibitors.
    Clarithromycin: (Major) Coadministration of felbamate and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
    Clobazam: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of felbamate. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and felbamate is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated. It should be noted that results of a population pharmacokinetic analysis showed that concurrent use of felbamate and clobazam did not significantly alter the kinetics of clobazam or its active metabolite at steady-state.
    Clopidogrel: (Major) Felbamate may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use clopidogrel and felbamate together with caution and monitor for reduced efficacy of clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Felbamate is a potent inhibitor of CYP2C19.
    Cobicistat: (Major) Coadministration of felbamate with cobicistat is not recommended. Concurrent use may decrease the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Felbamate is a CYP3A4 inducer, while cobicistat is a substrate of CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of felbamate with cobicistat is not recommended. Concurrent use may decrease the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Felbamate is a CYP3A4 inducer, while cobicistat is a substrate of CYP3A4. (Major) Coadministration of felbamate with elvitegravir is not recommended. Concurrent use may decrease the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Felbamate is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of felbamate with cobicistat is not recommended. Concurrent use may decrease the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Felbamate is a CYP3A4 inducer, while cobicistat is a substrate of CYP3A4. (Major) Coadministration of felbamate with elvitegravir is not recommended. Concurrent use may decrease the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Felbamate is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4.
    Cobimetinib: (Moderate) If concurrent use of cobimetinib and felbamate is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and felbamate is a weak inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
    Colesevelam: (Moderate) Colesevelam may decrease the bioavailability or felbamate if coadministered. To minimize potential for interactions, consider administering oral anticonvulsants such as felbamate at least 1 hour before or at least 4 hours after colesevelam.
    Dapsone: (Minor) The metabolism of dapsone may be accelerated when administered concurrently with felbamate, a known inducer of CYP3A4. Coadministration is expected to decrease the plasma concentration of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis). If these drugs must be administered together, closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia.
    Darunavir: (Major) Coadministration of felbamate with darunavir is not recommended. Plasma concentrations of darunavir may be reduced if these drugs are administered concurrently, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Felbamate is a CYP3A4 inducer; darunavir is a substrate of CYP3A4.
    Darunavir; Cobicistat: (Major) Coadministration of felbamate with cobicistat is not recommended. Concurrent use may decrease the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Felbamate is a CYP3A4 inducer, while cobicistat is a substrate of CYP3A4. (Major) Coadministration of felbamate with darunavir is not recommended. Plasma concentrations of darunavir may be reduced if these drugs are administered concurrently, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Felbamate is a CYP3A4 inducer; darunavir is a substrate of CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of felbamate with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in decreased plasma concentrations of dasabuvir, paritaprevir, and ritonavir. Felbamate is a mild inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are metabolized by this enzyme. Monitor for antiviral efficacy if these drugs are administered together. (Major) Concurrent administration of felbamate with ritonavir may result in decreased plasma concentrations of ritonavir. Felbamate is a mild inducer of the hepatic isoenzyme CYP3A4; ritonavir is metabolized by this enzyme. Monitor for antiviral efficacy if these drugs are administered together.
    Deferiprone: (Major) Avoid concomitant use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis, such as felbamate; however, if this is not possible, closely monitor the absolute neutrophil count and interrupt deferiprone therapy if neutropenia develops.
    Dolutegravir: (Major) Avoid concurrent use of dolutegravir with felbamate, as coadministration may result in decreased dolutegravir plasma concentrations. Felbamate is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
    Doxorubicin: (Major) Felbamate is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of felbamate and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Dronabinol, THC: (Moderate) Use caution if coadministration of dronabinol with felbamate is necessary, and monitor for a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; felbamate is a weak inducer of CYP3A4. Concomitant use may result in decreased plasma concentrations of dronabinol.
    Elbasvir; Grazoprevir: (Moderate) Caution is advised when administering elbasvir; grazoprevir with felbamate. Felbamate is a mild CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together may decrease the plasma concentrations of both elbasvir and grazoprevir, and could result in decreased virologic response.
    Elvitegravir: (Major) Coadministration of felbamate with elvitegravir is not recommended. Concurrent use may decrease the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Felbamate is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4.
    Erlotinib: (Major) Avoid the coadministration of erlotinib with felbamate if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Felbamate is a weak CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with felbamate may also decrease erlotinib exposure.
    Escitalopram: (Moderate) The plasma concentration of escitalopram, a CYP2C19 substrate, may be increased when administered concurrently with felbamate, a CYP2C19 inhibitor. If these drugs are used together, monitor for escitalopram-associated adverse reactions.
    Esomeprazole: (Minor) Felbamate may inhibit the CYP2C19 isoenzyme, leading to increased plasma levels of drugs that are substrates for the CYP2C19 isoenzyme, such as esomeprazole.
    Esomeprazole; Naproxen: (Minor) Felbamate may inhibit the CYP2C19 isoenzyme, leading to increased plasma levels of drugs that are substrates for the CYP2C19 isoenzyme, such as esomeprazole.
    Estrogens: (Major) Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs. Estrogens are metabolized by CYP3A4. Anticonvulsants that stimulate the activity of this enzyme include: barbiturates (including primidone), carbamazepine, felbamate, oxcarbazepine, phenytoin or fosphenytoin (and possibly ethotoin), and topiramate. The anticonvulsants mentioned may cause oral contraceptive failure, especially when low-dose estrogen regimens (e.g., ethinyl estradiol is < 50 mcg/day) are used. Epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism and the higher risk for oral contraceptive failure. During oral contraceptive failure, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. Women on OCs and enzyme-inducing anticonvulsant medications concurrently should report breakthrough bleeding to their prescribers. Oral contraceptive formulations containing higher dosages of ethinyl estradiol (i.e., 50 mcg ethinyl estradiol) may be needed to increase contraceptive efficacy. It may be prudent for some women who receive OCs concurrently with enzyme-inducing anticonvulsants to use an additional contraceptive method to protect against unwanted pregnancy. Higher dosages of oral contraceptives (e.g., ethinyl estradiol >= 50 mcg/day) or a second contraceptive method are typically suggested if women use an enzyme-inducing anti-epileptic drug or a barbiturate. Proper intake of folic acid should also be ensured.
    Ethanol: (Major) Additive CNS depression can occur if ethanol is consumed while taking felbamate. Regular ingestion of ethanol followed by abrupt discontinuation can provoke seizures.
    Etoposide, VP-16: (Moderate) Monitor for clinical efficacy of etoposide if used concomitantly with felbamate. Felbamate is a weak inducer of CYP3A4; etoposide, VP-16 is a CYP3A4 substrate. Coadministration of etoposide with a strong CYP3A4 inducer (phenytoin) resulted in increased etoposide clearance and reduced efficacy, as did coadministration with a weak inducer of CYP3A4 and P-glycoprotein (P-gp) (valproic acid).
    Gefitinib: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with felbamate. Gefitinib is metabolized significantly by CYP3A4 and felbamate is a weak CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
    Guanidine: (Minor) Bone marrow suppression is associated with guanidine therapy. Avoid concomitant use of other drugs known to cause bone marrow suppression such as felbamate.
    Hydantoins: (Moderate) Hydantoins are hepatic enzyme inducers and thus may accelerate the metabolism of several other anticonvulsants, including felbamate.
    Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as felbamate. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Irinotecan: (Major) Felbamate is a mild inducer of CYP3A4; irinotecan is a CYP3A4 substrate. Coadministration could potentially decrease irinotecan exposure, although coadministration of irinotecan with dexamethasone, a moderate CYP3A4 inducer, did not affect irinotecan pharmacokinetics. Monitor for efficacy of chemotherapy.
    Isavuconazonium: (Major) Avoid coadministration of isavuconazonium with felbamate. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of the hepatic isoenzyme CYP3A4; felbamate is an inducer of this enzyme. Coadministration may decrease the plasma concentrations of isavuconazole resulting in the potential for treatment failure.
    Isocarboxazid: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Ivabradine: (Major) Avoid coadministration of ivabradine and felbamate. Ivabradine is primarily metabolized by CYP3A4; felbamate is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Kava Kava, Piper methysticum: (Major) Any substances that act on the CNS, including anticonvulsants, may have a pharmacodynamic interaction with kava kava.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and felbamate may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; felbamate induces CYP3A4.
    Lisdexamfetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use lisdexamfetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
    Loperamide: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with felbamate. Loperamide is metabolized by the hepatic enzyme CYP3A4; felbamate is a mild inducer of this enzyme.
    Loperamide; Simethicone: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with felbamate. Loperamide is metabolized by the hepatic enzyme CYP3A4; felbamate is a mild inducer of this enzyme.
    Lopinavir; Ritonavir: (Major) Concurrent administration of felbamate with ritonavir may result in decreased plasma concentrations of ritonavir. Felbamate is a mild inducer of the hepatic isoenzyme CYP3A4; ritonavir is metabolized by this enzyme. Monitor for antiviral efficacy if these drugs are administered together.
    Maprotiline: (Major) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients carefully.
    Maraviroc: (Minor) Use caution if coadministration of maraviroc with felbamate is necessary, due to a possible decrease in maraviroc exposure. Maraviroc is a CYP3A substrate and felbamate is a CYP3A4 inducer. Monitor for a decrease in maraviroc efficacy with concomitant use.
    Mefloquine: (Moderate) Coadministration of mefloquine and anticonvulsants may result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the anticonvulsant serum concentration is recommended. Dosage adjustments may be required during and after therapy with mefloquine.
    Methsuximide: (Moderate) Concomitant use of felbamate and methsuximide may result in increased plasma concentrations of normethsuximide. The cause of the increase in normethsuximide concentrations is not known. Monitor concentrations of normethsuximide in patients treated with methsuximide and felbamate. Dosage adjustment of methsuximide may be required.
    Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
    Monoamine oxidase inhibitors: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Nintedanib: (Major) Felbamate is a mild inducer of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as felbamate should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of felbamate with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in decreased plasma concentrations of dasabuvir, paritaprevir, and ritonavir. Felbamate is a mild inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are metabolized by this enzyme. Monitor for antiviral efficacy if these drugs are administered together. (Major) Concurrent administration of felbamate with ritonavir may result in decreased plasma concentrations of ritonavir. Felbamate is a mild inducer of the hepatic isoenzyme CYP3A4; ritonavir is metabolized by this enzyme. Monitor for antiviral efficacy if these drugs are administered together.
    Pemoline: (Major) A reduction in seizure threshold has been reported following concomitant administration of pemoline with anticonvulsant agents. Dosage adjustments of anticonvulsants may be necessary during simultaneous use of these drugs.
    Phenelzine: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Phenobarbital: (Moderate) Concurrent administration of felbamate and other antiepileptic drugs results in changes in serum concentrations of both felbamate and the antiepileptic drugs. Felbamate increases the steady-state serum concentrations of phenobarbital.
    Phenothiazines: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant felbamate may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Praziquantel: (Major) In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. Therefore, use of praziquantel with felbamate, a CYP3A4 inducer, should be done with caution as concomitant use may produce therapeutically ineffective concentrations of praziquantel.
    Progestins: (Major) Based on very limited data, it appears felbamate can accelerate the clearance of the estrogen component of some oral contraceptives. Patients who experience breakthrough bleeding while receiving these drugs together should notify their prescribers. An alternate or additional form of contraception should be used during concomitant treatment. Additionally, patients taking non-oral combination contraceptives or estrogens or progestins for hormone replacement therapy may also experience reduced clinical efficacy; dosage adjustments may be necessary.
    Ribociclib: (Moderate) Use caution if ribociclib is coadministered with felbamate, as exposure to ribociclib may decrease, resulting in reduced efficacy. Ribociclib is extensively metabolized by CYP3A4 and felbamate is a CYP3A4 inducer.
    Ribociclib; Letrozole: (Moderate) Use caution if ribociclib is coadministered with felbamate, as exposure to ribociclib may decrease, resulting in reduced efficacy. Ribociclib is extensively metabolized by CYP3A4 and felbamate is a CYP3A4 inducer.
    Ritonavir: (Major) Concurrent administration of felbamate with ritonavir may result in decreased plasma concentrations of ritonavir. Felbamate is a mild inducer of the hepatic isoenzyme CYP3A4; ritonavir is metabolized by this enzyme. Monitor for antiviral efficacy if these drugs are administered together.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and felbamate may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Felbamate is a mild inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
    Selegiline: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and felbamate. Induction of CYP3A4 by felbamate may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Sofosbuvir; Velpatasvir: (Major) Use caution when administering velpatasvir with felbamate. Taking these drugs together may decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; felbamate is a weak inducer of CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Use caution when administering velpatasvir with felbamate. Taking these drugs together may decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; felbamate is a weak inducer of CYP3A4.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and felbamate; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and felbamate is a CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24hours) would decrease by 56% in cancer patients who received 14 days of sonidegib 200 mg/day with a moderate CYP3A inducer. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 69% in cancer patients who received sonidegib 200 mg/day with a moderate CYP3A inducer for 4 months.
    Tamoxifen: (Major) Felbamate is a mild CYP3A4 inducer and CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Felbamate may decrease the metabolism of tamoxifen to these metabolites, which can compromise efficacy. Plasma concentrations of tamoxifen and its active metabolites have been also reduced when coadministered other CYP3A4 inducers. If coadministration cannot be avoided, monitor for changes to the therapeutic effects of tamoxifen.
    Terbinafine: (Moderate) Caution is advised when administering terbinafine with felbamate. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may alter the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C19 and CYP3A4; felbamate is an inducer of CYP3A4 and an inhibitor of CYP2C19. Monitor patients for adverse reactions and breakthrough fungal infections if these drugs are coadministered.
    Topiramate: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant felbamate may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Tranylcypromine: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Trazodone: (Moderate) Trazodone can lower the seizure threshold of anticonvulsants, although the overall risk is low at therapeutic doses. Patients may require increased concentrations of anticonvulsants to achieve equivalent effects if trazodone is added.
    Tretinoin, ATRA: (Moderate) Felbamate may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. Monitor for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy.
    Tricyclic antidepressants: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and felbamate is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
    Valproic Acid, Divalproex Sodium: (Moderate) Felbamate has been shown to increase valproic acid serum concentrations, however the magnitude of this effect varies. Felbamate may interfere with valproic acid metabolism and should be administered cautiously to patients receiving valproic acid.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with felbamate is necessary, due to a possibly unpredictable effect on vandetanib efficacy and toxicity. Felbamate is a weak inducer of CYP3A4. In a crossover study (n = 12), coadministration of vandetanib with a strong CYP3A4 inducer, rifampicin, decreased the mean AUC of vandetanib by 40% (90% CI, 56% to 63%); a clinically meaningful change in the mean vandetanib Cmax was not observed. However, the AUC and Cmax of active metabolite, N-desmethyl-vandetanib, increased by 266% and 414%, respectively.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and felbamate; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and felbamate is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Vincristine Liposomal: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including felbamate. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Vincristine: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including felbamate. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and felbamate. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with felbamate, a mild CYP3A inducer.
    Voriconazole: (Minor) Voriconazole is a primary substrate of the CYP2C19 isoenzyme, and also is metabolized to a lesser extent by CYP3A4 and CYP2C9. Theoretically, CYP2C19 inhibitors, such as felbamate, may result in elevated voriconazole serum concentrations when coadministered. Felbamate is known to induce CYP3A4 as well as inhibit CYP2C19, so the net effect of this drug on voriconazole metabolism is not certain.

    PREGNANCY AND LACTATION

    Pregnancy

    Felbamate is classified as FDA pregnancy risk category C. There are no studies in pregnant women to determine the effect of felbamate on the fetus. It is not teratogenic in animal models. However, in rats, there was a decrease in pup weight and an increase in pup deaths during the post-birth lactation period; the cause for these deaths is not known. In addition, as a result of the synthesis process, felbamate could contain small amounts of two known animal carcinogens, the genotoxic compound ethyl carbamate (urethane) and the non-genotoxic compound methyl carbamate. The serious toxicities of felbamate, such as aplastic anemia, would also warrant that felbamate be used during pregnancy only if clearly needed. The effect of felbamate on labor and delivery in humans is unknown. Physicians are advised to recommend that pregnant patients receiving felbamate enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry.

    According to the manufacturer, felbamate is excreted into breast milk, but its effects on the infant are unknown. In rats, there was a decrease in pup weight and an increase in pup deaths during lactation; the reason for the deaths is not determined. Because of the serious toxicities associated with the drug, including aplastic anemia and hepatic failure, breast-feeding should generally be avoided during treatment with felbamate. Consider the benefits of breast-feeding, the risk of potential drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    The exact mechanism by which felbamate exerts its anticonvulsant activity is unknown. One possible mechanism involves N-methyl-D-aspartate (NMDA) receptors present in the central nervous system. Seizures are believed to be initiated and propagated by stimulation of the NMDA receptor, which may be regulated by activation of a receptor-gated calcium ion channel. These channels are regulated by the amino acid glycine. The binding of glycine to the NMDA receptor causes an increase in the frequency of NMDA receptor-mediated channel opening, which is important in the initiation and propagation of seizures. It is believed that felbamate antagonizes the effects of glycine by binding to the glycine-binding site of the NMDA receptor, thereby increasing the seizure threshold and preventing the spread of seizures. Felbamate does have relatively weak carbonic anhydrase inhibitory activity. Felbamate has no effect on benzodiazepine receptors, no interaction with GABA—A receptors, and no enhancement of GABA-induced chloride influx.

    PHARMACOKINETICS

    Felbamate is administered orally. The therapeutic range has not been established. Plasma protein binding ranges from 25—35%. About 15% of a dose is metabolized to agents that have insignificant anticonvulsant activity. Most (40—50%) of the administered dose is present in the urine unchanged, and 40% is recovered in the urine as unidentified metabolites and conjugates. Less than 5% of an orally administered dose is recovered in the feces. The plasma half-life of felbamate is 13—23 hours and is not changed after multiple doses.
     
    Affected cytochrome P450 isoenzymes: CYP2C19, CYP3A4
    Felbamate inhibits CYP2C19 and induces CYP3A4.
     

    Oral Route

    Absorption of felbamate after oral administration is approximately 90% and is not affected by food. It is similar for both the tablets and suspension. Time to peak serum concentration is 1—6 hours.