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Drug overview for FELBATOL (felbamate):
Generic name: FELBAMATE (fel-BAM-ate)
Drug class: Anticonvulsants
Therapeutic class: Central Nervous System Agents
Felbamate, a dicarbamate, is an anticonvulsant.
In July 1993, felbamate (Felbatol(R)) originally was approved by the FDA for use as monotherapy or in combination with other anticonvulsant agents in the management of partial seizures with or without secondary generalization in adults. Felbamate also was approved by FDA at that time for use in combination with other anticonvulsant agents in the management of partial and generalized seizures associated with Lennox-Gastaut syndrome in children and has been designated an orphan drug by FDA for the treatment of this latter syndrome. However, because felbamate has since been associated with marked increases in the incidences of aplastic anemia and acute hepatic failure, the drug is currently reserved for use only in patients who have not responded adequately to alternative safer treatments and whose seizure disorder is so severe that the risks of the drug are considered acceptable in light of the potential benefits.
Decisions about the potential benefits and risks of felbamate therapy generally should be made in consultation with appropriate hematologic and hepatic disease experts. (See Cautions.) Felbamate is currently available in the US for patients with severe, refractory seizure disorders in whom the benefits of the drug are considered to outweigh the potential risks of aplastic anemia and hepatic failure. However, clinicians should prescribe felbamate only if therapy with the drug is absolutely necessary.
Therapy with felbamate should be initiated or continued only after the risks associated with the drug have been discussed completely with the patient, parent, or guardian, and a written acknowledgment form has been obtained and signed by the patient and physician. All cases of aplastic anemia or acute hepatic failure associated with felbamate therapy should be reported promptly to the manufacturer or to FDA MedWatch by phone (800-FDA-1088) or website (http://www.fda.gov/Safety/MedWatch/). Although the comparative efficacy of therapeutically effective dosages remains to be established, the anticonvulsant potential of felbamate in patients with partial seizures with or without secondary generalization has been established in studies comparing therapeutic dosages of felbamate with relatively low dosages of valproic acid.
In 2 such studies, adult patients with partial seizures were randomly assigned to receive either felbamate up to 3.6 g daily administered in 4 divided doses or valproic acid 15 mg/kg daily during a 112-day treatment period. Both studies were designed only to demonstrate the anticonvulsant activity of felbamate monotherapy using low-dosage valproate as a control; this study design, described as a low-dose active-control trial, is intended to avoid the interpretational difficulties of no-difference (i.e., equivalent) therapeutic outcomes in studies of investigational anticonvulsant agents and therefore is not intended to determine comparative efficacy.
The primary variable used to measure anticonvulsant activity was the number of patients in each group who met at least one of the following escape criteria and consequently exited the study: (1) a twofold increase in average monthly seizure frequency, (2) a twofold increase in the highest 2-day seizure frequency, (3) a single generalized tonic-clonic seizure if none occurred during the baseline period, or (4) a prolongation of generalized seizure duration (serial seizures or status epilepticus) deemed by the investigator to require intervention. In these studies, 14-40% of patients receiving felbamate met escape criteria and exited the study compared with 78-90% of patients receiving low-dosage valproic acid, indicating that felbamate alone has anticonvulsant activity in patients with partial seizures; however, because of the study design, no conclusions regarding comparative efficacy with valproic acid can be made. Felbamate also may potentiate the anticonvulsant activity of other agents in the management of refractory partial seizures.
In a double-blind, placebo-controlled crossover trial, patients with refractory partial seizures who received felbamate administered concomitantly with phenytoin and carbamazepine had fewer seizures during each treatment sequence than patients who received placebo with phenytoin and carbamazepine. However, in a 3-period, crossover study of patients with complex partial seizures receiving carbamazepine in combination with either felbamate (usually 3 g daily) or placebo, felbamate-induced reductions in plasma concentrations of carbamazepine were believed to have contributed to the lack of effect of the drug on seizure frequency. Among patients who underwent reduction or discontinuance of a standard regimen of anticonvulsant therapy during evaluation for surgery of an intractable seizure disorder, those who subsequently received concomitant felbamate had greater time to onset of fourth seizure than patients who received placebo.
In children with Lennox-Gastaut syndrome, maximum tolerated dosage of felbamate (up to 45 mg/kg (not exceeding 3.6 g) daily) has reduced the frequency of atonic seizures, generalized tonic-clonic seizures, and total seizures when added to the patient's standard regimen of anticonvulsant therapy. Improvements in quality-of-life parameters (increased alertness and verbal responsiveness) also have been reported by parents or guardians in such children. The efficacy of monotherapy or combination therapy with felbamate for the management of partial seizures and Lennox-Gastaut syndrome reportedly is not influenced by patient gender.
Generic name: FELBAMATE (fel-BAM-ate)
Drug class: Anticonvulsants
Therapeutic class: Central Nervous System Agents
Felbamate, a dicarbamate, is an anticonvulsant.
In July 1993, felbamate (Felbatol(R)) originally was approved by the FDA for use as monotherapy or in combination with other anticonvulsant agents in the management of partial seizures with or without secondary generalization in adults. Felbamate also was approved by FDA at that time for use in combination with other anticonvulsant agents in the management of partial and generalized seizures associated with Lennox-Gastaut syndrome in children and has been designated an orphan drug by FDA for the treatment of this latter syndrome. However, because felbamate has since been associated with marked increases in the incidences of aplastic anemia and acute hepatic failure, the drug is currently reserved for use only in patients who have not responded adequately to alternative safer treatments and whose seizure disorder is so severe that the risks of the drug are considered acceptable in light of the potential benefits.
Decisions about the potential benefits and risks of felbamate therapy generally should be made in consultation with appropriate hematologic and hepatic disease experts. (See Cautions.) Felbamate is currently available in the US for patients with severe, refractory seizure disorders in whom the benefits of the drug are considered to outweigh the potential risks of aplastic anemia and hepatic failure. However, clinicians should prescribe felbamate only if therapy with the drug is absolutely necessary.
Therapy with felbamate should be initiated or continued only after the risks associated with the drug have been discussed completely with the patient, parent, or guardian, and a written acknowledgment form has been obtained and signed by the patient and physician. All cases of aplastic anemia or acute hepatic failure associated with felbamate therapy should be reported promptly to the manufacturer or to FDA MedWatch by phone (800-FDA-1088) or website (http://www.fda.gov/Safety/MedWatch/). Although the comparative efficacy of therapeutically effective dosages remains to be established, the anticonvulsant potential of felbamate in patients with partial seizures with or without secondary generalization has been established in studies comparing therapeutic dosages of felbamate with relatively low dosages of valproic acid.
In 2 such studies, adult patients with partial seizures were randomly assigned to receive either felbamate up to 3.6 g daily administered in 4 divided doses or valproic acid 15 mg/kg daily during a 112-day treatment period. Both studies were designed only to demonstrate the anticonvulsant activity of felbamate monotherapy using low-dosage valproate as a control; this study design, described as a low-dose active-control trial, is intended to avoid the interpretational difficulties of no-difference (i.e., equivalent) therapeutic outcomes in studies of investigational anticonvulsant agents and therefore is not intended to determine comparative efficacy.
The primary variable used to measure anticonvulsant activity was the number of patients in each group who met at least one of the following escape criteria and consequently exited the study: (1) a twofold increase in average monthly seizure frequency, (2) a twofold increase in the highest 2-day seizure frequency, (3) a single generalized tonic-clonic seizure if none occurred during the baseline period, or (4) a prolongation of generalized seizure duration (serial seizures or status epilepticus) deemed by the investigator to require intervention. In these studies, 14-40% of patients receiving felbamate met escape criteria and exited the study compared with 78-90% of patients receiving low-dosage valproic acid, indicating that felbamate alone has anticonvulsant activity in patients with partial seizures; however, because of the study design, no conclusions regarding comparative efficacy with valproic acid can be made. Felbamate also may potentiate the anticonvulsant activity of other agents in the management of refractory partial seizures.
In a double-blind, placebo-controlled crossover trial, patients with refractory partial seizures who received felbamate administered concomitantly with phenytoin and carbamazepine had fewer seizures during each treatment sequence than patients who received placebo with phenytoin and carbamazepine. However, in a 3-period, crossover study of patients with complex partial seizures receiving carbamazepine in combination with either felbamate (usually 3 g daily) or placebo, felbamate-induced reductions in plasma concentrations of carbamazepine were believed to have contributed to the lack of effect of the drug on seizure frequency. Among patients who underwent reduction or discontinuance of a standard regimen of anticonvulsant therapy during evaluation for surgery of an intractable seizure disorder, those who subsequently received concomitant felbamate had greater time to onset of fourth seizure than patients who received placebo.
In children with Lennox-Gastaut syndrome, maximum tolerated dosage of felbamate (up to 45 mg/kg (not exceeding 3.6 g) daily) has reduced the frequency of atonic seizures, generalized tonic-clonic seizures, and total seizures when added to the patient's standard regimen of anticonvulsant therapy. Improvements in quality-of-life parameters (increased alertness and verbal responsiveness) also have been reported by parents or guardians in such children. The efficacy of monotherapy or combination therapy with felbamate for the management of partial seizures and Lennox-Gastaut syndrome reportedly is not influenced by patient gender.
DRUG IMAGES
FELBATOL 600 MG TABLET
FELBATOL 400 MG TABLET
The following indications for FELBATOL (felbamate) have been approved by the FDA:
Indications:
Complex-partial epilepsy
Lennox-Gastaut epilepsy
Partial epilepsy treatment adjunct
Simple-partial epilepsy
Professional Synonyms:
Automatic epilepsy
Complex focal epilepsy
Complex focal seizures
Complex local seizures
Complex partial epilepsy
Complex partial seizures
Complex psychomotor epilepsy
Complex psychomotor seizure
Complex temporal lobe epilepsy
Complex temporal lobe seizures
Elementary focal seizures
Elementary partial seizures
Epilepsy of Lennox Gastaut syndrome
Partial onset seizures treatment adjunct
Partial seizures treatment adjunct
Psychic epilepsy
Psychomotor epilepsy
Psychomotor seizure
Simple focal epilepsy
Simple focal seizures
Simple local seizures
Simple partial epilepsy
Simple psychomotor epilepsy
Simple psychomotor seizures
Simple temporal lobe epilepsy
Simple temporal lobe seizures
Temporal lobe epilepsy
Temporal lobe seizure
Indications:
Complex-partial epilepsy
Lennox-Gastaut epilepsy
Partial epilepsy treatment adjunct
Simple-partial epilepsy
Professional Synonyms:
Automatic epilepsy
Complex focal epilepsy
Complex focal seizures
Complex local seizures
Complex partial epilepsy
Complex partial seizures
Complex psychomotor epilepsy
Complex psychomotor seizure
Complex temporal lobe epilepsy
Complex temporal lobe seizures
Elementary focal seizures
Elementary partial seizures
Epilepsy of Lennox Gastaut syndrome
Partial onset seizures treatment adjunct
Partial seizures treatment adjunct
Psychic epilepsy
Psychomotor epilepsy
Psychomotor seizure
Simple focal epilepsy
Simple focal seizures
Simple local seizures
Simple partial epilepsy
Simple psychomotor epilepsy
Simple psychomotor seizures
Simple temporal lobe epilepsy
Simple temporal lobe seizures
Temporal lobe epilepsy
Temporal lobe seizure
The following dosing information is available for FELBATOL (felbamate):
Dosage of felbamate must be carefully and slowly adjusted according to individual requirements and response. Felbamate should be withdrawn slowly because abrupt discontinuance of the drug may precipitate seizures. (See Cautions: Precautions and Contraindications.)
When felbamate is used as initial monotherapy, therapy should begin with a low dosage of the drug and slowly increased. When felbamate is added to an existing anticonvulsant regimen, the drug should be added gradually while dosage of the other anticonvulsant(s) is decreased to reduce the risk of adverse effects from drug interactions. When transferring patients from combination therapy to monotherapy with felbamate, dosage of felbamate should be increased gradually while dosages of other anticonvulsant agents should be decreased gradually and discontinued.
The initial dosage of felbamate as monotherapy or adjunctive therapy (i.e., in combination with other anticonvulsants) for the management of partial seizures in adults and adolescents 14 years of age or older is 1.2 g daily administered in 3 or 4 divided doses. Subsequent dosage may be increased gradually based on clinical response; recommended titration increments and schedules are based on whether the patient is receiving felbamate as initial monotherapy or adjunctive therapy, or converting from combination therapy to felbamate monotherapy.
The majority of patients in both monotherapy and adjunctive trials received a felbamate dosage of 3.6 g daily. More rapid titration of felbamate dosage than that currently suggested by the manufacturer occasionally has been employed.
For patients with partial seizures receiving felbamate as initial monotherapy, the initial felbamate dosage may be increased by 600-mg daily increments at 2-week intervals to 2.4 g daily administered in 3 or 4 divided doses or until optimum clinical response is obtained. Clinicians are advised to titrate previously untreated patients under close medical supervision.
If adequate seizure control has not been achieved and further increases in monotherapy dosage are considered clinically necessary, felbamate dosage may be titrated further to 3.6 g daily. Felbamate has not been evaluated systematically as initial monotherapy.
For patients with partial seizures converting from combination therapy to felbamate monotherapy, the initial felbamate dosage may be increased by 1.2-g daily increments at weekly intervals up to 3.6 g daily administered in 3 or 4 divided doses.
As felbamate replaces the existing anticonvulsant regimen, dosage(s) of the other anticonvulsant(s) should be gradually reduced (by 33% of the baseline dosage in the first week, then an additional 33% or less of the baseline dosage in the second week, and then as clinically indicated in the third week) and discontinued.
For patients with partial seizures receiving felbamate as adjunctive therapy with other anticonvulsant agents (e.g., phenytoin, valproic acid, phenobarbital, carbamazepine), the initial felbamate dosage may be increased by 1.2-g daily increments at weekly intervals up to 3.6 g daily administered in 3 or 4 divided doses.
Dosage(s) of the other anticonvulsant(s) must be reduced initially by at least 20%; further reductions in dosage(s) of concomitant anticonvulsant(s) may be necessary to avoid adverse effects caused by drug interactions.
The usual initial dosage of felbamate as adjunctive therapy for the management of Lennox-Gastaut syndrome in children 2-14 years of age is 15 mg/kg daily administered in 3 or 4 divided doses. Dosage may be increased by 15 mg/kg daily at weekly intervals to 45 mg/kg daily administered in 3 or 4 divided doses. As felbamate is added to existing anticonvulsants (e.g., phenytoin, valproic acid, phenobarbital, carbamazepine), the dosage(s) of the other anticonvulsant(s) must be decreased initially by at least 20%; further reductions in dosage(s) of concomitant anticonvulsant(s) may be necessary to avoid adverse effects caused by drug interactions.
The manufacturer states that initial and maintenance dosages of felbamate should be reduced by 50% in patients with renal impairment. Adjunctive therapy with drugs that affect plasma felbamate concentrations, especially other anticonvulsants, may warrant further reductions in felbamate daily dosage in patients with renal impairment.
Felbamate should not be used in patients with hepatic impairment.
If felbamate is used in geriatric patients, the initial dosage usually should be at the low end of the dosage range. (See Cautions: Geriatric Precautions.)
When felbamate is used as initial monotherapy, therapy should begin with a low dosage of the drug and slowly increased. When felbamate is added to an existing anticonvulsant regimen, the drug should be added gradually while dosage of the other anticonvulsant(s) is decreased to reduce the risk of adverse effects from drug interactions. When transferring patients from combination therapy to monotherapy with felbamate, dosage of felbamate should be increased gradually while dosages of other anticonvulsant agents should be decreased gradually and discontinued.
The initial dosage of felbamate as monotherapy or adjunctive therapy (i.e., in combination with other anticonvulsants) for the management of partial seizures in adults and adolescents 14 years of age or older is 1.2 g daily administered in 3 or 4 divided doses. Subsequent dosage may be increased gradually based on clinical response; recommended titration increments and schedules are based on whether the patient is receiving felbamate as initial monotherapy or adjunctive therapy, or converting from combination therapy to felbamate monotherapy.
The majority of patients in both monotherapy and adjunctive trials received a felbamate dosage of 3.6 g daily. More rapid titration of felbamate dosage than that currently suggested by the manufacturer occasionally has been employed.
For patients with partial seizures receiving felbamate as initial monotherapy, the initial felbamate dosage may be increased by 600-mg daily increments at 2-week intervals to 2.4 g daily administered in 3 or 4 divided doses or until optimum clinical response is obtained. Clinicians are advised to titrate previously untreated patients under close medical supervision.
If adequate seizure control has not been achieved and further increases in monotherapy dosage are considered clinically necessary, felbamate dosage may be titrated further to 3.6 g daily. Felbamate has not been evaluated systematically as initial monotherapy.
For patients with partial seizures converting from combination therapy to felbamate monotherapy, the initial felbamate dosage may be increased by 1.2-g daily increments at weekly intervals up to 3.6 g daily administered in 3 or 4 divided doses.
As felbamate replaces the existing anticonvulsant regimen, dosage(s) of the other anticonvulsant(s) should be gradually reduced (by 33% of the baseline dosage in the first week, then an additional 33% or less of the baseline dosage in the second week, and then as clinically indicated in the third week) and discontinued.
For patients with partial seizures receiving felbamate as adjunctive therapy with other anticonvulsant agents (e.g., phenytoin, valproic acid, phenobarbital, carbamazepine), the initial felbamate dosage may be increased by 1.2-g daily increments at weekly intervals up to 3.6 g daily administered in 3 or 4 divided doses.
Dosage(s) of the other anticonvulsant(s) must be reduced initially by at least 20%; further reductions in dosage(s) of concomitant anticonvulsant(s) may be necessary to avoid adverse effects caused by drug interactions.
The usual initial dosage of felbamate as adjunctive therapy for the management of Lennox-Gastaut syndrome in children 2-14 years of age is 15 mg/kg daily administered in 3 or 4 divided doses. Dosage may be increased by 15 mg/kg daily at weekly intervals to 45 mg/kg daily administered in 3 or 4 divided doses. As felbamate is added to existing anticonvulsants (e.g., phenytoin, valproic acid, phenobarbital, carbamazepine), the dosage(s) of the other anticonvulsant(s) must be decreased initially by at least 20%; further reductions in dosage(s) of concomitant anticonvulsant(s) may be necessary to avoid adverse effects caused by drug interactions.
The manufacturer states that initial and maintenance dosages of felbamate should be reduced by 50% in patients with renal impairment. Adjunctive therapy with drugs that affect plasma felbamate concentrations, especially other anticonvulsants, may warrant further reductions in felbamate daily dosage in patients with renal impairment.
Felbamate should not be used in patients with hepatic impairment.
If felbamate is used in geriatric patients, the initial dosage usually should be at the low end of the dosage range. (See Cautions: Geriatric Precautions.)
Felbamate is administered orally (as tablets or oral suspension). The manufacturer states that both the commercially available tablet and oral suspension have been shown to be bioequivalent to the capsule formulation used in clinical trials; the pharmacokinetic profiles of the tablet and oral suspension are similar. Food does not appear to affect absorption of felbamate tablets; the effect of food on absorption of the oral suspension has not been evaluated.
Patients who are currently receiving or beginning therapy with felbamate and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior. (See Cautions: Nervous System Effects and see Cautions: Precautions and Contraindications.)
Patients who are currently receiving or beginning therapy with felbamate and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior. (See Cautions: Nervous System Effects and see Cautions: Precautions and Contraindications.)
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| FELBATOL 400 MG TABLET | Maintenance | Adults take 1 tablet (400 mg) by oral route 3 times per day |
| FELBATOL 600 MG TABLET | Maintenance | Adults take 1 tablet (600 mg) by oral route 3 times per day |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| FELBAMATE 400 MG TABLET | Maintenance | Adults take 1 tablet (400 mg) by oral route 3 times per day |
| FELBAMATE 600 MG TABLET | Maintenance | Adults take 1 tablet (600 mg) by oral route 3 times per day |
The following drug interaction information is available for FELBATOL (felbamate):
There are 0 contraindications.
There are 8 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Selected Anticonvulsants; Barbiturates/Contraceptives SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Barbiturates, hydantoins, and primidone may increase the metabolism of the contraceptives via CYP3A4 induction. CLINICAL EFFECTS: May observe reduced contraceptive effects such as breakthrough bleeding, spotting, or pregnancy. Effects may be seen several days after discontinuation of the anticonvulsant or barbiturate. In addition, topiramate has been associated with an increased risk of birth defects, including cleft palate. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: To avoid pregnancy, additional or alternative means of non-hormonal contraception should be utilized. Depo medroxyprogesterone may be an alternative, since its effectiveness is not decreased by anticonvulsants. Patients receiving perampanel at doses of 12 mg/day should use alternative contraception methods, such as an intra-uterine device or condom. Patients receiving topiramate may observe decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg per day. Patients taking topiramate and estrogen containing or progestin-only contraceptives should be asked to report any change in their bleeding patterns.(20) Patients taking the combination of phentermine/topiramate for weight loss should be counseled that break-through bleeding may occur but is not expected to increase the risk of pregnancy. Instruct patients to report changes in bleeding patterns to their physician and to continue to take their hormonal contraceptive. Patients should not rely on hormonal contraceptives (other than implants or IUD) alone, but may use them in combination with a barrier contraceptive. It is necessary to use effective contraception with phentermine/topiramate, because the topiramate content of the product can cause birth defects. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant. DISCUSSION: Decreased effectiveness of oral contraceptives, characterized by breakthrough bleeding and amenorrhea have been documented. Through August, 2010, Australia's Therapeutic Goods Association had received 32 reports of contraceptive failure leading to pregnancy as a result of a suspected interaction between etonogestrel implants and carbamazepine. In a randomized, open-label study in healthy women, concurrent topiramate (50 mg daily to 200 mg daily) and Ortho Novum 1/35 (ethinyl estradiol and norethindrone) resulted in no changes in levels of ethinyl estradiol or norethindrone. However, in another study, concurrent topiramate at doses of 200 mg daily, 400 mg daily, and 800 mg daily with valproic acid decreased the area-under-curve (AUC) of ethinyl estradiol by 18%, 21%, and 30%, respectively. There were no changes in norethindrone levels. The US manufacturer of topiramate states that the possibility of decreased contraceptive effectiveness should be considered. At doses of 12 mg/day, perampanel decreased the maximum concentration (Cmax) and AUC of levonorgestrel by 40% each. The Cmax of ethinyl estradiol was decreased by 18%. There were no effects on ethinyl estradiol AUC. Doses of perampanel of 4 mg/day and 8 mg/day had no effect on contraceptive levels. The combination of phentermine/topiramate (15 mg/92 mg for 15 days) increased the Cmax and AUC of norethindrone by 22% and 16%, respectively. The Cmax and AUC of ethinyl estradiol decreased 8% and 16%, respectively. Because contraceptive efficacy is primarily determined by the progestin component, no effect on contraceptive efficacy is expected, although breakthrough bleeding may occur. The effectiveness of depo medroxyprogesterone is not decreased by anticonvulsants or barbiturates. |
2-METHOXYESTRADIOL, AFIRMELLE, ALTAVERA, ALYACEN, AMETHIA, AMETHYST, ANNOVERA, APRI, ARANELLE, ASHLYNA, AUBRA, AUBRA EQ, AUROVELA, AUROVELA 24 FE, AUROVELA FE, AVIANE, AYUNA, AZURETTE, BALCOLTRA, BALZIVA, BEYAZ, BLISOVI 24 FE, BLISOVI FE, BRIELLYN, CAMILA, CAMRESE, CAMRESE LO, CAZIANT, CHARLOTTE 24 FE, CHATEAL EQ, CRYSELLE, CYRED, CYRED EQ, DASETTA, DAYSEE, DEBLITANE, DESOGESTR-ETH ESTRAD ETH ESTRA, DIETHYLSTILBESTROL, DOLISHALE, DROSPIRENONE-ETH ESTRA-LEVOMEF, DROSPIRENONE-ETHINYL ESTRADIOL, ELINEST, ELURYNG, EMZAHH, ENILLORING, ENPRESSE, ENSKYCE, ERRIN, ESTARYLLA, ESTRADIOL, ESTRADIOL BENZOATE, ESTRADIOL CYPIONATE, ESTRADIOL HEMIHYDRATE, ESTRADIOL HEMIHYDRATE MICRO, ESTRADIOL MICRONIZED, ESTRADIOL VALERATE, ESTRIOL, ESTRIOL MICRONIZED, ESTRONE, ETHINYL ESTRADIOL, ETHYNODIOL-ETHINYL ESTRADIOL, ETONOGESTREL-ETHINYL ESTRADIOL, FALMINA, FEIRZA, FEMLYV, FINZALA, GEMMILY, HAILEY, HAILEY 24 FE, HAILEY FE, HALOETTE, HEATHER, ICLEVIA, INCASSIA, ISIBLOOM, JAIMIESS, JASMIEL, JENCYCLA, JOLESSA, JOYEAUX, JULEBER, JUNEL, JUNEL FE, JUNEL FE 24, KAITLIB FE, KALLIGA, KARIVA, KELNOR 1-35, KELNOR 1-50, KURVELO, LARIN, LARIN 24 FE, LARIN FE, LAYOLIS FE, LEENA, LESSINA, LEVONEST, LEVONORG-ETH ESTRAD ETH ESTRAD, LEVONORG-ETH ESTRAD-FE BISGLYC, LEVONORGESTREL-ETH ESTRADIOL, LEVORA-28, LO LOESTRIN FE, LO-ZUMANDIMINE, LOESTRIN, LOESTRIN FE, LOJAIMIESS, LORYNA, LOW-OGESTREL, LUTERA, LYLEQ, LYZA, MARLISSA, MERZEE, MIBELAS 24 FE, MICROGESTIN, MICROGESTIN FE, MILI, MINZOYA, MONO-LINYAH, NATAZIA, NECON, NEXPLANON, NEXTSTELLIS, NIKKI, NORA-BE, NORELGESTROMIN-ETH ESTRADIOL, NORETHIN-ETH ESTRA-FERROUS FUM, NORETHINDRON-ETHINYL ESTRADIOL, NORETHINDRONE, NORETHINDRONE-E.ESTRADIOL-IRON, NORGESTIMATE-ETHINYL ESTRADIOL, NORTREL, NUVARING, NYLIA, OCELLA, ORTHO TRI-CYCLEN, ORTHO-NOVUM, PHILITH, PIMTREA, PORTIA, RECLIPSEN, RIVELSA, SAFYRAL, SETLAKIN, SHAROBEL, SIMLIYA, SIMPESSE, SLYND, SPRINTEC, SRONYX, SYEDA, TARINA 24 FE, TARINA FE, TARINA FE 1-20 EQ, TAYTULLA, TILIA FE, TRI-ESTARYLLA, TRI-LEGEST FE, TRI-LINYAH, TRI-LO-ESTARYLLA, TRI-LO-MARZIA, TRI-LO-MILI, TRI-LO-SPRINTEC, TRI-MILI, TRI-SPRINTEC, TRI-VYLIBRA, TRI-VYLIBRA LO, TRIVORA-28, TULANA, TURQOZ, TWIRLA, TYBLUME, VALTYA, VELIVET, VESTURA, VIENVA, VIORELE, VOLNEA, VYFEMLA, VYLIBRA, WERA, WYMZYA FE, XARAH FE, XELRIA FE, XULANE, YASMIN 28, YAZ, ZAFEMY, ZARAH, ZOVIA 1-35, ZUMANDIMINE |
| Clopidogrel/Felbamate; Stiripentol SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Felbamate and stiripentol may inhibit the metabolism of clopidogrel to its active form by CYP2C19.(1,3) CLINICAL EFFECTS: Concurrent use of felbamate or stiripentol may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.(1,3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of clopidogrel states that concurrent use of inhibitors of CYP2C19, such as felbamate and stiripentol, should be avoided.(1) The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19 are poor metabolizers of this isoenzyme. Consider alternatives to felbamate or stiripentol in patients stabilized on clopidogrel, or alternatives to clopidogrel in patients stabilized on felbamate or stiripentol. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity. DISCUSSION: In a randomized, cross-over study in healthy subjects, ketoconazole (another CYP2C19 inhibitor, 400 mg daily) decreased the maximum concentration (Cmax) of the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg daily) by 61%. The area-under-curve (AUC) of the active metabolite of clopidogrel was decreased by 22% following the loading dose and by 29% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 28% following the loading dose and by 33% during the maintenance dose.(3) In a cross-over study in 72 healthy subjects, simultaneous administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) and clopidogrel (300 mg loading dose, followed by 75 mg daily) decreased the AUC of the active metabolite of clopidogrel by 46% following the loading dose and by 42% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 47% following the loading dose and by 30% during the maintenance dose. In a cross-over study in 72 healthy subjects, administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) 12 hours after clopidogrel (300 mg loading dose, followed by 75 mg daily) produced similar effects.(1) |
CLOPIDOGREL, CLOPIDOGREL BISULFATE, PLAVIX |
| Citalopram (Greater Than 20 mg)/Select CYP2C19 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Citalopram is primarily metabolized by the CYP2C19 isoenzyme.(1) CLINICAL EFFECTS: Concurrent use of an agent that inhibits CYP2C19 may result in elevated levels of and toxicity from citalopram, including including risks for serotonin syndrome or prolongation of the QTc interval.(1-5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, poor metabolizer status at CYP2C19, or higher blood concentrations of citalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. PATIENT MANAGEMENT: The dose of citalopram should be limited to 20 mg in patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4) Evaluate the patient for other drugs, diseases and conditions which increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(1,2) Weigh the specific benefits versus risks for each patient. The US manufacturer recommends ECG monitoring for citalopram patients with congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging medications or receiving concurrent therapy.(4) Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. DISCUSSION: Concurrent use of citalopram (40 mg daily) and cimetidine (400 mg twice daily) for 8 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, and tecovirimat.(7,8) |
CELEXA, CITALOPRAM HBR |
| Selected Anticonvulsants/Selected Barbiturates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Phenobarbital, and perhaps other barbiturates, induce multiple metabolic enzymes including CYP1A2, CYP2C9, CYP2C19, CYP3A4, and glucuronidation (UGT) pathways. Felbamate, oxcarbazepine, and valproic acid are metabolized by one or more of these induced pathways. Valproic acid may inhibit the CYP2C9 mediated metabolism of phenobarbital, and possibly other barbiturates. Felbamate and oxcarbazepine may inhibit the CYP2C19 mediated metabolism of barbiturates. CLINICAL EFFECTS: Lower felbamate, oxcarbazepine, and valproic acid concentrations may lead to diminished efficacy, e.g loss of seizure control, or new onset/more difficult to control manic episodes. Higher barbiturate concentrations may lead to increased sedation or further CNS depression. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: For patients stabilized on barbiturates, monitor for increased barbiturate levels approximately 4 to 7 days after initiation or after an increase in the dose of felbamate or oxcarbazepine. The US manufacturer of felbamate recommends that the dosage of phenobarbital be reduced by 20-33% when felbamate is initiated. The US manufacturer of extended release oxcarbazepine recommends initiating extended release oxcarbazepine at 900 mg once daily in adults and 12-15 mg/kg once daily (not to exceed 900 mg per day in the first week) in pediatric patients. If a barbiturate is added to a patient stabilized on felbamate or oxcarbazepine, the dose of felbamate or oxcarbazepine may need to be increased. Onset of induction is gradual and may not be maximal for days or weeks. Initiation of barbiturate therapy in a patient already stabilized on valproic acid will lead to a gradual lowering of valproic acid concentrations over approximately 1 to 3 weeks. Valproate concentrations could fall by 50%. Monitor valproate levels and adjust the dose as needed to maintain therapeutic efficacy. Due to valproic acid inhibition of barbiturate metabolism, consider starting barbiturate therapy at a lower than usual dose and increase as tolerated. Closely monitor therapy for needed adjustments in the barbiturate dose in patients maintained on valproate therapy when initiating these agents. Conversely, due to enzyme induction, larger than expected valproic acid doses may be required to achieve therapeutic benefit. Educate the patient regarding possible adverse effects and the need for valproate measurements to assure treatment efficacy. If the barbiturate is discontinued in a patient stabilized on felbamate, oxcarbazepine, and valproic acid therapy, felbamate, oxcarbazepine, and valproic acid concentrations will increase over 1 to 4 weeks. Monitor serum levels and adjust dosages as needed. DISCUSSION: Prescribing information for oxcarbazepine states that phenobarbital doses of 100 to 150 mg daily decreased the mean concentration of its active metabolite (eslicarbazepine) 25%. In a study in 12 healthy males, administration of felbamate (2400 mg daily) increased phenobarbital levels by 25%. In a study in 24 healthy subjects, administration of felbamate (2400 mg daily) increased phenobarbital (100 mg daily) area-under-curve (AUC) and maximum concentration (Cmax) levels by 22% and 24%, respectively. In clinical trials, patients receiving concurrent phenobarbital were found to have felbamate concentrations that were 29% lower than patients not receiving concurrent phenobarbital. In contrast, a retrospective review of felbamate levels found no effect by barbiturates. In a case report, felbamate was initiated and titrated to 50 mg/kg/day over three weeks. At this time, the patient's phenobarbital dosage was decreased 13% (from 230 mg/daily to 200 mg/day). Despite this, the patient's phenobarbital level increased 42% and the patient developed neurotoxicity. The patient's phenobarbital dosage was further reduced to 35% of the original dosage (to 150 mg daily) and the patient's phenobarbital levels returned to therapeutic range. Valproate metabolites are formed via three major pathways: mitochondrial beta-oxidation (40%), glucuronidation (30-50%), and CYP P-450 (10%). Barbiturates induce several glucuronidation and CYP450 pathways, but not mitochondrial pathways. Manufacturer prescribing for valproic acid states that concomitant primidone or phenobarbital therapy may double valproic acid clearance. An interaction study in health subjects administered valproate 250mg BID for 14 days with a single 60 mg dose of phenobarbital leading to a 50% increase in half-life and a 30% decrease in the clearance of phenobarbital. |
ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, DONNATAL, FIORICET, FIORICET WITH CODEINE, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, TENCON |
| Siponimod/Selected Moderate CYP2C9 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inhibitors of CYP2C9 may inhibit the metabolism of siponimod.(1) CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP2C9 may result in elevated levels of and clinical effects of siponimod, including immunosuppression and increased risk of infection.(1) Concurrent use of siponimod with immunosuppressive or immune-modulating agents, such as asciminib, may result in an additive risk and increased risk of serious infections. PREDISPOSING FACTORS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may increase the effects of the interaction. PATIENT MANAGEMENT: Concurrent use of an inhibitor of CYP2C9 with siponimod is not recommended in patients also taking a strong or moderate inhibitor of CYP3A4.(1) Review the patient's therapy for concurrent use of strong or moderate inhibitors of CYP3A4 prior to initiating siponimod. DISCUSSION: Siponimod is metabolized by CYP2C9 (79.3%) and CYP3A4 (18.5%). Concurrent use of fluconazole (a dual moderate inhibitor of CYP2C9 and CYP3A4, 200 mg at steady state) in healthy subjects with the CYP2C9*1/*1 genotype increased the area-under-curve (AUC) of siponimod (4 mg single dose) by 2-fold. Siponimod half-life increased by 50%. Fluconazole increased siponimod AUC by 2-fold to 4-fold across all CYP2C9 genotypes.(1) Selected moderate CYP2C9 inhibitors linked to this monograph include: apazone, asciminib, benzbromarone, cannabidiol, felbamate, miconazole, milk thistle, nitisinone, oxandrolone, phenylbutazone, piperine, silibinin, and sulfaphenazole.(2) |
MAYZENT |
| Sodium Iodide I 131/Myelosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1) DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1) |
HICON, SODIUM IODIDE I-131 |
| Ulipristal/Selected Anticonvulsants SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Eslicarbazepine, mephenytoin, oxcarbazepine, rufinamide, and topiramate may induce the metabolism of ulipristal by CYP3A4.(1,2) CLINICAL EFFECTS: Concurrent use or use of eslicarbazepine, mephenytoin, oxcarbazepine, rufinamide, or topiramate within the previous 2-3 weeks may result in decreased levels and effectiveness of ulipristal.(1,2) In addition, topiramate has been associated with an increased risk of birth defects, including cleft palate.(3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US and UK manufacturers of ulipristal states that concurrent use with CYP3A4 inducers such as eslicarbazepine, mephenytoin, oxcarbazepine, rufinamide, or topiramate is not recommended. Decreased effectiveness of ulipristal may occur even 2-3 weeks after discontinuation of these agents.(1,2) DISCUSSION: CYP3A4 inducers may decrease levels and effectiveness of ulipristal. Enzyme induction may take 2-3 weeks to wear off. Plasma levels of ulipristal may be reduced even if the CYP3A4 inducer was discontinued in the previous 2-3 weeks.(1) Concurrent administration of ulipristal 30 mg and rifampin 600 mg, another CYP3A4 inducer, for 9 days decreased the maximum concentration (Cmax) and area-under-the-curve (AUC) by 90% and 93%, respectively. The Cmax and AUC of monodemethyl-ulipristal decreased by 84% and 90%, respectively.(2) |
ELLA |
| Mavacamten/Weak CYP2C19 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Weak CYP2C19 inhibitors may inhibit the metabolism of mavacamten.(1-3) CLINICAL EFFECTS: Concurrent use of weak CYP2C19 inhibitors increases plasma exposure of mavacamten which may increase the incidence and severity of adverse reactions of mavacamten.(1-3) PREDISPOSING FACTORS: CYP2C19 rapid and ultrarapid metabolizers may experience an increased incidence or severity of adverse effects.(1-3) PATIENT MANAGEMENT: The US manufacturer of mavacamten recommends to initiate mavacamten at the recommended starting dosage of 5 mg orally once daily in patients who are on stable therapy with a weak CYP2C19 inhibitor. Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on mavacamten treatment and intend to initiate a weak CYP2C19 inhibitor. Schedule clinical and an echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate mavacamten until 12 weeks after inhibitor initiation.(1) Avoid initiation of concomitant weak CYP2C19 inhibitors in patients who are on stable treatment with 2.5 mg of mavacamten because a lower dose is not available.(1) For short-term use (e.g. 1 week), interrupt mavacamten therapy for the duration of the weak CYP2C19 inhibitor. After therapy with the weak CYP2C19 inhibitor is discontinued, mavacamten may be reinitiated at the previous dose immediately upon discontinuation.(1) The Canadian manufacturer of mavacamten recommends additional monitoring when concurrent use of weak CYP2C19 inhibitors is warranted. Adjust the dose of mavacamten based on clinical assessment.(2) The UK manufacturer of mavacamten states no dose adjustment is necessary with weak CYP2C19 inhibitors. Monitor left ventricular ejection fraction (LVEF) in 4 weeks then resume usual monitoring schedule.(3) DISCUSSION: Concomitant use of mavacamten (15 mg) with omeprazole (20 mg), a weak CYP2C19 inhibitor, once daily increased mavacamten area-under-curve (AUC) by 48% with no effect on maximum concentration (Cmax) in healthy CYP2C19 normal metabolizers and rapid metabolizers.(1) Weak CYP2C19 inhibitors include: armodafinil, cimetidine, enasidenib, eslicarbazepine, felbamate, givosiran, isoniazid, obeticholic acid, osilodrostat, piperine, rucaparib, tecovirimat.(4,5) |
CAMZYOS |
There are 6 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Felbamate/Carbamazepine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Unknown. However, felbamate probably increases the metabolism of carbamazepine to the epoxide metabolite and/or inhibits the conversion of the epoxide metabolite of carbamazepine to the diol metabolite. In addition, carbamazepine increases the metabolism of felbamate. CLINICAL EFFECTS: Both serum carbamazepine and felbamate concentrations may be decreased reducing their therapeutic effects. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Serum concentrations of both drugs should be monitored and patients should be observed for changes in seizure control if therapy with either agent is started, stopped or altered. Adjust therapy as indicated. The US manufacturer of felbamate recommends decreasing the dosage of carbamazepine by 20% when initiating felbamate therapy. DISCUSSION: In patients stabilized on carbamazepine monotherapy, addition of felbamate produced a decrease in plasma carbamazepine concentrations. The effect on serum carbamazepine concentrations was evident following one week of felbamate coadministration, reached a plateau between the second and fourth weeks and persisted during concomitant therapy with both anticonvulsants. Serum carbamazepine concentrations returned to original levels within 3 weeks of discontinuing felbamate. Although serum levels of carbamazepine decreased, the active epoxide metabolite of carbamazepine increased by 46%. Addition of carbamazepine to regimen of patients receiving felbamate results in a decrease in felbamate plasma concentrations. |
CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, EPITOL, EQUETRO, TEGRETOL, TEGRETOL XR |
| Felbamate/Valproic Acid SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Felbamate may inhibit the CYP2C19 metabolism of valproic acid. CLINICAL EFFECTS: The addition of felbamate may result in elevated levels and toxicity from valproic acid.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of felbamate recommends decreasing the dosage of valproic acid by 20% during the initiation of felbamate therapy.(1) DISCUSSION: Administration of felbamate to 10 epileptic patients stabilized on valproic acid resulted in a dose related increase in felbamate area-under-curve (AUC) and maximum concentration (Cmax).(2) In a study in 4 subjects with epilepsy receiving valproate, valproate minimum concentration (Cmin) increased by 24% and 52% following the addition of felbamate at dosages of 1200 mg/day an 2400 mg/day, respectively.(1) In a study in 18 healthy subjects receiving valproate (400 mg/day for 21 days) and felbamate (days 8-21 at 1200 mg/day, 2400 mg/day, 3000mg/day, or 3600 mg/day) increased valproate Cmax by 38-72% and AUC by 93-108% (except for the 1200 mg/day dose) depending on felbamate dose. Valproate clearance was reduced by 34-54% depending on felbamate dose.(3) In a study in 10 children on valproic acid with felbamate (mean dose 18.5 mg/kg/day), the Cmin and AUC were increased and the valproic acid clearance was reduced 21%.(4) In a study in 10 subjects with epilepsy stabilized on valproic acid (9.5 - 31.7 mg/kg/day) receiving felbamate (600 mg or 1200 mg twice a day) resulted in an increase in Cmax and AUC of 34-55% and 27-54% and a reduction in clearance of 22-33%.(5) |
DEPAKOTE, DEPAKOTE ER, DEPAKOTE SPRINKLE, DIVALPROEX SODIUM, DIVALPROEX SODIUM ER, SODIUM VALPROATE, VALPROATE SODIUM, VALPROIC ACID |
| Citalopram (Less than or Equal To 20 mg)/Selected CYP2C19 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Citalopram is primarily metabolized by the CYP2C19 isoenzyme.(1) CLINICAL EFFECTS: Concurrent use of an agent that inhibits CYP2C19 may result in elevated levels of and toxicity from citalopram, including including risks for serotonin syndrome or prolongation of the QTc interval.(1-5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, poor metabolizer status at CYP2C19, or higher blood concentrations of citalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. PATIENT MANAGEMENT: The dose of citalopram should be limited to 20 mg in patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4) Evaluate the patient for other drugs, diseases and conditions which increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, hypocalcemia, hypomagnesemia, discontinue other QT prolonging drugs) when possible.(1,2) Weigh the specific benefits versus risks for each patient. The US manufacturer recommends ECG monitoring for citalopram patients with congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging medications or receiving concurrent therapy.(4) Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. DISCUSSION: Concurrent use of citalopram (40 mg daily) and cimetidine (400 mg twice daily) for 8 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, and tecovirimat.(7,8) |
CELEXA, CITALOPRAM HBR |
| Escitalopram (Greater Than 15 mg)/Selected CYP2C19 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: At lower systemic concentrations, escitalopram is primarily metabolized by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of an agent which significantly inhibits CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated concentrations and toxicity from escitalopram, including risks for serotonin syndrome or prolongation of the QTc interval.(1,5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3) PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status at CYP2C19, concurrent use of more than one agent known to cause QT prolongation, or with higher blood concentrations of escitalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. PATIENT MANAGEMENT: Evaluate patient for other drugs, diseases and conditions which may further increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(2,3) It would be prudent to limit the escitalopram dose to 10 mg daily in patients with QT prolonging risk factors who also receive concurrent therapy with selected CYP2C19 inhibitors.(5) Weigh the specific benefits versus risks for each patient. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. DISCUSSION: A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was conducted; a change of 10 msec for upper bound of the 95% confidence level is the threshold for regulatory concern. In this study, changes to the upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar to expected steady state concentrations in 2C19 poor metabolizers following a 20 mg escitalopram dose.(1) In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of CYP2C19 was administered daily for 6 days. On day 5 a single dose of escitalopram 20 mg was also administered; the area-under-curve (AUC) of escitalopram was increased by 50%. Manufacturer prescribing information recommends a maximum citalopram dose of 20mg daily in patients receiving CYP2C19 inhibitors.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, and tipranavir.(4) |
ESCITALOPRAM OXALATE, LEXAPRO |
| Slt Anticonvulsants/Hydantoins; Anticonvulsant Barbiturates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Phenobarbital, and perhaps other barbiturates, induce multiple metabolic enzymes including CYP1A2, CYP2C9, CYP2C19, CYP3A4, and glucuronidation (UGT) pathways. Phenytoin, and perhaps other hydantoins, induce multiple metabolic enzymes including CYP2C9, CYP2C19, CYP3A4 and UGT pathways. Felbamate, oxcarbazepine, and valproic acid are metabolized by one or more of these induced pathways. Valproic acid may inhibit the CYP2C9 mediated metabolism of phenobarbital, possibly other barbiturates, and hydantoins. Felbamate and oxcarbazepine may inhibit the CYP2C19 mediated metabolism of phenytoin and barbiturates. Primidone is metabolized to phenobarbital. CLINICAL EFFECTS: Lower felbamate, oxcarbazepine, and valproic acid concentrations may lead to diminished efficacy, e.g loss of seizure control, or new onset/more difficult to control manic episodes. Higher barbiturate and/or hydantoin concentrations may lead to increased sedation or further CNS depression. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: For patients stabilized on phenytoin or barbiturates, monitor for increased phenytoin or barbiturate levels approximately 4 to 7 days after initiation or after an increase in the dose of felbamate or oxcarbazepine. The US manufacturer of felbamate recommends that the dosage of phenobarbital and phenytoin be reduced by 20-33% when felbamate is initiated. The US manufacturer of extended release oxcarbazepine recommends initiating extended release oxcarbazepine at 900 mg once daily in adults and 12-15 mg/kg once daily (not to exceed 900 mg per day in the first week) in pediatric patients. If phenytoin or a barbiturate is added to a patient stabilized on felbamate or oxcarbazepine, the dose of felbamate or oxcarbazepine may need to be increased. Onset of induction is gradual and may not be maximal for days or weeks. Initiation of barbiturate or hydantoin therapy in a patient already stabilized on valproic acid will lead to a gradual lowering of valproic acid concentrations over approximately 1 to 3 weeks. Valproate concentrations could fall by 50%. Monitor valproate levels and adjust the dose as needed to maintain therapeutic efficacy. Due to valproic acid inhibition of barbiturate and hydantoin metabolism, consider starting barbiturate or hydantoin therapy at a lower than usual dose and increase as tolerated. Closely monitor therapy for needed adjustments in the barbiturate or hydantoin dose in patients maintained on valproate therapy when initiating these agents. Conversely, due to enzyme induction, larger than expected valproic acid doses may be required to achieve therapeutic benefit. Educate the patient regarding possible adverse effects and the need for valproate measurements to assure treatment efficacy. If the barbiturate or hydantoin is discontinued in a patient stabilized on felbamate, oxcarbazepine, and valproic acid therapy, felbamate, oxcarbazepine, and valproic acid concentrations will increase over 1 to 4 weeks. Monitor serum levels and adjust dosages as needed. DISCUSSION: In interaction studies, oxcarbazepine dosage > 1200 mg daily increased phenytoin concentrations 30 to 40%; phenytoin doses of 250 to 500mg daily decreased eslicarbazepine or oxcarbazepine concentrations approximately 30%. In a study of lower dosage (900 mg daily) oxcarbazepine and phenytoin, no effects on phenytoin levels were seen. Prescribing information for oxcarbazepine states that phenobarbital doses of 100 to 150 mg daily decreased the mean concentration of its active metabolite (eslicarbazepine) 25%. In a study in 10 patients with epilepsy maintained on phenytoin therapy, phenytoin minimum concentration (Cmin) increased by 24% and 47% following the addition of felbamate at dosages of 1200 mg/day and 1800 mg/day, respectively. Phenytoin dosage reductions of 40% were necessary in 8 of the 10 subjects in order to achieve a felbamate dosage of 3600 mg/day while limiting adverse effects and maintain phenytoin levels. In another clinical trial, decreasing the dosage of phenytoin by 20% at the initiation of felbamate therapy resulted in no significant changes in phenytoin levels. Phenytoin has been shown to almost double the clearance of felbamate, resulting in a 45% decrease in felbamate levels. In a study in 12 healthy males, administration of felbamate (2400 mg daily) increased phenobarbital levels by 25%. In a study in 24 healthy subjects, administration of felbamate (2400 mg daily) increased phenobarbital (100 mg daily) area-under-curve (AUC) and maximum concentration (Cmax) levels by 22% and 24%, respectively. In clinical trials, patients receiving concurrent phenobarbital were found to have felbamate concentrations that were 29% lower than patients not receiving concurrent phenobarbital. In contrast, a retrospective review of felbamate levels found no effect by barbiturates. In a case report, felbamate was initiated and titrated to 50 mg/kg/day over three weeks. At this time, the patient's phenobarbital dosage was decreased 13% (from 230 mg/daily to 200 mg/day). Despite this, the patient's phenobarbital level increased 42% and the patient developed neurotoxicity. The patient's phenobarbital dosage was further reduced to 35% of the original dosage (to 150 mg daily) and the patient's phenobarbital levels returned to therapeutic range. Valproate metabolites are formed via three major pathways: mitochondrial beta-oxidation (40%), glucuronidation (30-50%), and CYP P-450 (10%). Barbiturates induce several glucuronidation and CYP450 pathways, but not mitochondrial pathways. Manufacturer prescribing for valproic acid states that concomitant primidone or phenobarbital therapy may double valproic acid clearance. An interaction study in health subjects administered valproate 250mg BID for 14 days with a single 60 mg dose of phenobarbital leading to a 50% increase in half-life and a 30% decrease in the clearance of phenobarbital. In most patients the active form of phenytoin (the unbound drug) is not significantly changed by valproic acid. Decreased serum phenytoin concentrations have been reported, as have symptoms of phenytoin toxicity. Increases in frequency of seizures have also been reported. Patients receiving phenytoin and valproic acid concurrently tend to have lower serum valproic acid concentrations than patients taking valproic acid alone. Concomitant administration of valproate (400 mg three times a day) with phenytoin (250 mg) in 7 healthy volunteers increased the free fraction of phenytoin by 60%. The total plasma clearance and volume of distrubution of phenytoin increased 30% with concomitant valproate. |
CEREBYX, DILANTIN, DILANTIN-125, FOSPHENYTOIN SODIUM, MYSOLINE, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIMIDONE, SEZABY |
| Escitalopram (Less Than or Equal To 15 mg)/Selected CYP2C19 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: At lower systemic concentrations, escitalopram is primarily metabolized by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of an agent which significantly inhibits CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated concentrations and toxicity from escitalopram, including risks for serotonin syndrome or prolongation of the QTc interval.(1,5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3) PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status at CYP2C19, concurrent use of more than one agent known to cause QT prolongation, or with higher blood concentrations of escitalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. PATIENT MANAGEMENT: Evaluate patient for other drugs, diseases and conditions which may further increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(2,3) It would be prudent to limit the escitalopram dose to 10 mg daily in patients with QT prolonging risk factors who also receive concurrent therapy with selected CYP2C19 inhibitors.(5) Weigh the specific benefits versus risks for each patient. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. DISCUSSION: A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was conducted; a change of 10 msec for upper bound of the 95% confidence level is the threshold for regulatory concern. In this study, changes to the upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar to expected steady state concentrations in 2C19 poor metabolizers following a 20 mg escitalopram dose.(1) In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of CYP2C19 was administered daily for 6 days. On day 5 a single dose of escitalopram 20 mg was also administered; the area-under-curve (AUC) of escitalopram was increased by 50%. Manufacturer prescribing information recommends a maximum citalopram dose of 20mg daily in patients receiving CYP2C19 inhibitors.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, and tipranavir.(4) |
ESCITALOPRAM OXALATE, LEXAPRO |
The following contraindication information is available for FELBATOL (felbamate):
Drug contraindication overview.
No enhanced Contraindications information available for this drug.
No enhanced Contraindications information available for this drug.
There are 7 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Anemia |
| Aplastic anemia |
| Disease of liver |
| Hepatic failure |
| Lactation |
| Leukopenia |
| Thrombocytopenic disorder |
There are 2 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Porphyria |
| Suicidal ideation |
There are 2 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Depression |
| Kidney disease with reduction in glomerular filtration rate (GFr) |
The following adverse reaction information is available for FELBATOL (felbamate):
Adverse reaction overview.
No enhanced Common Adverse Effects information available for this drug.
No enhanced Common Adverse Effects information available for this drug.
There are 32 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Fever Gait abnormality |
Aggressive behavior Agitation Altered mental status Ataxia CNS toxicity Mood changes Skin rash Tremor |
| Rare/Very Rare |
|---|
|
Acute hepatic failure Agranulocytosis Anaphylaxis Aplastic anemia Blood dyscrasias Bone marrow depression Drug-induced psychosis Dyspnea Facial edema IgA vasculitis Leukopenia Lymphadenopathy Nasal congestion Pancytopenia Pruritus of skin Qualitative platelet disorder Skin photosensitivity Stevens-johnson syndrome Suicidal ideation Supraventricular tachycardia Thrombocytopenic disorder Urticaria |
There are 24 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abdominal pain with cramps Anorexia Constipation Disorder of the digestive system Dizziness Dysgeusia Dyspepsia Headache disorder Insomnia Nausea Vomiting |
Blurred vision Diarrhea Diplopia Drowsy Nervousness Rhinitis Symptoms of anxiety Upper respiratory infection Weight loss |
| Rare/Very Rare |
|---|
|
Accidental fall Behavioral disorders Palpitations Tachycardia |
The following precautions are available for FELBATOL (felbamate):
No enhanced Pediatric Use information available for this drug.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Reproduction studies in rats and rabbits receiving felbamate doses of up to 13.9 and 4.2 times, respectively, the human daily dose of the drug on mg/kg basis (3 and less than 2 times, respectively, the human daily dose on a mg/m2 basis) did not reveal evidence of teratogenicity; however, in rats, there was a decrease in pup weight and an increase in pup deaths during lactation.
The cause of these deaths is not known. The dose at which there was no effect on rat pup mortality was 6.9 times the human dose on a mg/kg basis (1.5 times the human dose on a mg/m2 basis).
Felbamate crosses the placenta in rats. There are, however, no adequate and controlled studies to date using the drug in pregnant women, and the effect of felbamate on labor and delivery in humans also is not known. Felbamate should be used during pregnancy only when clearly needed.
Women who are pregnant while receiving felbamate should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334; registry information also is available at http://www.aedpregnancyregistry.org.
The cause of these deaths is not known. The dose at which there was no effect on rat pup mortality was 6.9 times the human dose on a mg/kg basis (1.5 times the human dose on a mg/m2 basis).
Felbamate crosses the placenta in rats. There are, however, no adequate and controlled studies to date using the drug in pregnant women, and the effect of felbamate on labor and delivery in humans also is not known. Felbamate should be used during pregnancy only when clearly needed.
Women who are pregnant while receiving felbamate should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334; registry information also is available at http://www.aedpregnancyregistry.org.
Felbamate is distributed into milk. Since the potential effect in nursing infants is not known, some clinicians state that felbamate probably should not be used during breast-feeding.
No enhanced Geriatric Use information available for this drug.
The following prioritized warning is available for FELBATOL (felbamate):
WARNING: Severe (sometimes fatal) blood/bone marrow problems (such as low red/white blood cells and platelets) and liver problems have occurred with felbamate. Felbamate should be used only by people with severe seizures (epilepsy) that cannot be controlled with other medications. Do not use this drug if you have liver problems.
Discuss the risks and benefits with your doctor before starting felbamate. Tell your doctor right away if you have signs of infection (such as sore throat that doesn't go away, fever, chills), signs of anemia (such as unusual tiredness), easy bruising/bleeding, or signs of liver problems (such as nausea/vomiting that doesn't stop, stomach/abdominal pain, yellowing eyes/skin, dark urine). Usually, people who have liver problems while taking this drug should not start taking it again.
Your doctor will check certain blood tests (liver function, complete blood count) and may have you see a doctor who treats blood/bone marrow problems before you start felbamate and while you use this drug. Blood/bone marrow problems may also occur after you stop taking the drug. Blood tests may be needed for some time after you stop taking felbamate. Keep all medical and lab appointments.
WARNING: Severe (sometimes fatal) blood/bone marrow problems (such as low red/white blood cells and platelets) and liver problems have occurred with felbamate. Felbamate should be used only by people with severe seizures (epilepsy) that cannot be controlled with other medications. Do not use this drug if you have liver problems.
Discuss the risks and benefits with your doctor before starting felbamate. Tell your doctor right away if you have signs of infection (such as sore throat that doesn't go away, fever, chills), signs of anemia (such as unusual tiredness), easy bruising/bleeding, or signs of liver problems (such as nausea/vomiting that doesn't stop, stomach/abdominal pain, yellowing eyes/skin, dark urine). Usually, people who have liver problems while taking this drug should not start taking it again.
Your doctor will check certain blood tests (liver function, complete blood count) and may have you see a doctor who treats blood/bone marrow problems before you start felbamate and while you use this drug. Blood/bone marrow problems may also occur after you stop taking the drug. Blood tests may be needed for some time after you stop taking felbamate. Keep all medical and lab appointments.
The following icd codes are available for FELBATOL (felbamate)'s list of indications:
| Complex-partial epilepsy | |
| G40.0 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset |
| G40.00 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable |
| G40.009 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable, without status epilepticus |
| G40.01 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, intractable |
| G40.019 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, intractable, without status epilepticus |
| G40.2 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures |
| G40.20 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, not intractable |
| G40.209 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, not intractable, without status epilepticus |
| G40.21 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, intractable |
| G40.219 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, intractable, without status epilepticus |
| Lennox-gastaut epilepsy | |
| G40.81 | Lennox-gastaut syndrome |
| G40.812 | Lennox-gastaut syndrome, not intractable, without status epilepticus |
| G40.814 | Lennox-gastaut syndrome, intractable, without status epilepticus |
| Partial epilepsy treatment adjunct | |
| G40.0 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset |
| G40.00 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable |
| G40.009 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable, without status epilepticus |
| G40.01 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, intractable |
| G40.019 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, intractable, without status epilepticus |
| G40.1 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures |
| G40.10 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable |
| G40.109 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable, without status epilepticus |
| G40.11 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, intractable |
| G40.119 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, intractable, without status epilepticus |
| G40.2 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures |
| G40.20 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, not intractable |
| G40.209 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, not intractable, without status epilepticus |
| G40.21 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, intractable |
| G40.219 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, intractable, without status epilepticus |
| Simple-partial epilepsy | |
| G40.0 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset |
| G40.00 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable |
| G40.009 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable, without status epilepticus |
| G40.01 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, intractable |
| G40.019 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, intractable, without status epilepticus |
| G40.1 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures |
| G40.10 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable |
| G40.109 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable, without status epilepticus |
| G40.11 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, intractable |
| G40.119 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, intractable, without status epilepticus |
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