CLASSES

Anticonvulsants, Carbamates

BOXED WARNING

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 after 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.

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

MAXIMUM DOSAGE

3600 mg/day PO.

3600 mg/day PO.

3600 mg/day PO.

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

DOSING CONSIDERATIONS

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

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.

STORAGE

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

CONTRAINDICATIONS / PRECAUTIONS

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.

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 after 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.

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.

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.

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.

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. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to felbamate; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.

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.

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 of felbamate can precipitate seizures.

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. 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, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If felbamate must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; the use of any anticonvulsant for any condition should be based on confirmation of the condition and its potential cause(s). Determine effectiveness and tolerability by evaluating symptoms, and use these as the basis for dosage adjustment for most patients. Therapeutic drug monitoring is not required or available for most anticonvulsants. Serum medication concentrations (when available) may assist in identifying toxicity. Monitor the treated patient for drug efficacy and side effects. Anticonvulsants can cause a variety of side effects; some adverse reactions can increase the risk of 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 as outlined in the OBRA guidelines.[60742]

ADVERSE REACTIONS

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
hepatotoxicity / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
hemolytic-uremic syndrome / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
hemolytic anemia / 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

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
jaundice / Delayed / Incidence not known
hepatitis / 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

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 / 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: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with felbamate; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. 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; 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.
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.
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.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of felbamate with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and felbamate is a CYP2C19 inhibitor.
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.
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.
Darunavir; Cobicistat; 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 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.
Dextromethorphan; 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.
Dolutegravir: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with felbamate; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Felbamate is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with felbamate; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Felbamate is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Dolutegravir; Rilpivirine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with felbamate; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Felbamate is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Doxorubicin Liposomal: (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.
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: (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; Cobicistat; 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.
Elvitegravir; Cobicistat; 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.
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.
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) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression. (Moderate) Additive CNS depression can occur if alcohol is consumed while taking felbamate. Regular ingestion of alcohol followed by abrupt discontinuation can provoke seizures.
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.
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) Additive CNS depression is possible if MAOIs and felbamate are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction including those that prolong PR interval, such as sodium channel blocking anticonvulsants (e.g., felbamate), because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
Lansoprazole; Amoxicillin; 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.
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.
Lidocaine; Epinephrine: (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.
Lidocaine; Prilocaine: (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.
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.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with felbamate due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure. Mavacamten is a CYP2C19 substrate and felbamate is a moderate CYP2C19 inhibitor.
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. Patients may also experience additive sedation or dizziness, or changes in moods and behaviors.
Methsuximide: (Moderate) Monitor concentrations of N-desmethylmethsuximide in patients treated with methsuximide and felbamate. Dosage adjustment of methsuximide may be required. Concomitant use of felbamate and methsuximide may result in increased plasma concentrations of N-desmethylmethsuximide. The cause of the increase in N-desmethylmethsuximide concentrations is not known.
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) Additive CNS depression is possible if MAOIs and felbamate are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
Naproxen; 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.
Nirmatrelvir; 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.
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.
Phenelzine: (Moderate) Additive CNS depression is possible if MAOIs and felbamate are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
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.
Phenobarbital; Hyoscyamine; Atropine; 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.
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.
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.
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.
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.
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.
Tranylcypromine: (Moderate) Additive CNS depression is possible if MAOIs and felbamate are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
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: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. 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.
Vasopressin, ADH: (Moderate) Monitor hemodynamics and adjust the dose of vasopressin as needed when used concomitantly with drugs suspected of causing syndrome of inappropriate antidiuretic hormone (SIADH), such as felbamate. Use together may increase the pressor and antidiuretic effects of vasopressin.
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.
Vonoprazan; Amoxicillin; 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.
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.
Zonisamide: (Moderate) Concomitant use of zonisamide with felbamate may increase the risks of hyperammonemia and encephalopathy. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.

PREGNANCY AND LACTATION

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. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to felbamate; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.

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.