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Special Alerts
Antiepileptics: Increased Risk of Suicidal Behavior or Ideation - Updated: December 2008
The U.S. Food and Drug Administration (FDA) has issued an update following the completion of its analysis concerning the risk of suicidality (suicidal behavior or ideation) observed during clinical trials of various antiepileptic drugs (compared to placebo) in the treatment of epilepsy, psychiatric disorders, and other conditions. The pooled analysis of 199 clinical trials involving 11 antiepileptic drugs (carbamazepine, divalproex sodium, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, zonisamide) as either monotherapy or as adjuvant therapy showed that patients receiving an antiepileptic had a 0.43% risk of suicidal behavior/ideation compared to 0.24% of patients receiving placebo. As a result of the findings, the FDA will require that the product labeling of the entire class of antiepileptics include a warning concerning the risk of suicidality, and a medication guide be developed informing patients of this risk.
Additional information may be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm074939.htm
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
CarBAMazepine may be confused with OXcarbazepine
Carbatrol® may be confused with Cartrol®
Epitol® may be confused with Epinal®
Tegretol®, Tegretol®-XR may be confused with Mebaral®, Tegrin®, Toprol-XL®, Toradol®, Trental®
Pronunciation
(kar ba MAZ e peen)
U.S. Brand Names
Index Terms
Generic Available
Yes: Excludes capsule (extended release), tablet (extended release)
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Carbatrol®, Tegretol®, Tegretol®-XR: Partial seizures with complex symptomatology (psychomotor, temporal lobe), generalized tonic-clonic seizures (grand mal), mixed seizure patterns, trigeminal neuralgia
Equetro®: Acute manic and mixed episodes associated with bipolar 1 disorder
Use: Dental
Pain relief of trigeminal or glossopharyngeal neuralgia
Use: Unlabeled/Investigational
Treatment of resistant schizophrenia, ethanol withdrawal, restless leg syndrome, post-traumatic stress disorders
Pregnancy Risk Factor
D
Pregnancy Considerations
Crosses the placenta. Dysmorphic facial features, cranial defects, cardiac defects, spina bifida, IUGR, and multiple other malformations reported. Epilepsy itself, number of medications, genetic factors, or a combination of these probably influences the teratogenicity of anticonvulsant therapy. Benefit:risk ratio usually favors continued use during pregnancy and breast-feeding. Contraceptives may be rendered less effective by the coadministration of carbamazepine; alternative methods of contraception should be considered.Patients exposed to carbamazepine during pregnancy are encouraged to enroll themselves into the AED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.
Lactation
Enters breast milk/not recommended (AAP rates “compatible”)
Breast-Feeding Considerations
Carbamazepine and its metabolites are found in breast milk. The manufacturer does not recommend use while breast-feeding. However, AAP rates this medication "compatible" in breast-feeding.
Contraindications
Hypersensitivity to carbamazepine, tricyclic antidepressants, or any component of the formulation; bone marrow depression; with or within 14 days of MAO inhibitor use; concurrent use of nefazodone
Warnings/Precautions
Boxed warnings:
• Blood dyscrasias: See “Concerns related to adverse effects” below.
• Dermatologic reactions: See “Special populations” below.
Concerns related to adverse effects:
• Blood dyscrasias: [U.S. Boxed Warning]: Potentially fatal blood cell abnormalities have been reported following treatment. A spectrum of hematologic effects has been reported with use (eg, agranulocytosis, aplastic anemia, neutropenia, leukopenia, thrombocytopenia, pancytopenia, and anemias); patients with a previous history of adverse hematologic reaction to any drug may be at increased risk. Early detection of hematologic change is important; advise patients of early signs and symptoms including fever, sore throat, mouth ulcers, infections, easy bruising, petechial or purpuric hemorrhage.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Dermatologic reactions: Severe reactions, including toxic epidermal necrolysis and Stevens-Johnson syndromes, although rarely reported, have resulted in fatalities; use caution and screen for genetic susceptibility in Asian patients (see "Special populations" below); drug should be discontinued if there are any signs of hypersensitivity.
• Multiorgan hypersensitivity reactions: Potentially serious, sometimes fatal multiorgan hypersensitivity reactions have been reported with some antiepileptic drugs; monitor for signs and symptoms of possible disparate manifestations associated with lymphatic, hepatic, renal, and/or hematologic organ systems; gradual discontinuation and conversion to alternate therapy may be required.
• Psychiatric effects: May activate latent psychosis and/or cause confusion or agitation; elderly patients may be at an increased risk for psychiatric effects.
• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ?24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.
Disease-related concerns:
• Anticholinergic sensitivity: Has mild anticholinergic activity; use with caution in patients with sensitivity to anticholinergic effects (urinary retention, increased intraocular pressure, constipation).
• Cardiovascular disease: May cause conduction abnormalities; use caution in patients with underlying ECG abnormalities, pre-existing cardiac damage, or patients who are at risk for conduction abnormalities.
• Hepatic impartment: Use with caution in patients with hepatic impairment or history of hepatic porphyria; rare cases of hepatic failure have been reported.
• Renal impairment: Use with caution in patients with renal impairment.
Concurrent drug therapy issues:
• High potential for interactions: Use with caution in patients taking strong CYP3A4 induces or inhibitors. Carbamazepine may significantly induce many CYP450 enzymes, including 1A2, 2B6, 2C9, 2C19, and 3A4; use with caution with medications significantly metabolized through these pathways.
• Nefazodone: Coadministration yields insufficient plasma levels of nefazodone to achieve a therapeutic effect; concurrent use is contraindicated.
• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.
Special populations:
• Asian ancestry: [U.S. Boxed Warning]: Patients of Asian descent should be screened for the variant HLA-B*1502 allele prior to initiating therapy. This genetic variant has been associated with a significantly increased risk of developing Stevens-Johnson syndrome and/or toxic epidermal necrolysis. Patients with a positive result should not be started on carbamazepine.
• Elderly: There may be an increased risk of SIADH-like syndrome in the elderly; may activate latent psychosis, confusion, or agitation.
• Pediatrics: Exacerbation of certain seizure types have been seen after initiation of therapy in children with mixed seizure disorders.
Dosage form specific issues:
• Suspension: Administration of the suspension will yield higher peak and lower trough serum levels than an equal dose of the tablet form; consider a lower starting dose given more frequently (same total daily dose) when using the suspension.
Other warnings/precautions:
• Appropriate use: Not effective in absence, myoclonic, or akinetic seizures; carbamazepine administration may increase the frequency of seizures in patients with these types of seizures
• Bipolar disorder use: The smallest effective dose is suggested for use in bipolar disorder to reduce the risk for overdose/suicide; high-risk patients should be monitored for suicidal ideations. Prescription should be written for the smallest quantity consistent with good patient care. Actuation of latent psychosis is possible.
• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.
Adverse Reactions
Frequency not defined, unless otherwise specified.
Cardiovascular: Arrhythmias, AV block, bradycardia, chest pain (bipolar use), CHF, edema, hyper-/hypotension, lymphadenopathy, syncope, thromboembolism, thrombophlebitis
Central nervous system: Amnesia (bipolar use), anxiety (bipolar use), aseptic meningitis (case report), ataxia (bipolar use 15%), confusion, depression (bipolar use), dizziness (bipolar use 44%), fatigue, headache (bipolar use 22%), sedation, slurred speech, somnolence (bipolar use 32%)
Dermatologic: Alopecia, alterations in skin pigmentation, erythema multiforme, exfoliative dermatitis, photosensitivity reaction, pruritus (bipolar use 8%), purpura, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Chills, fever, hyponatremia, syndrome of inappropriate ADH secretion (SIADH)
Gastrointestinal: Abdominal pain, anorexia, constipation, diarrhea, dyspepsia (bipolar use), gastric distress, nausea (bipolar use 29%), pancreatitis, vomiting (bipolar use 18%), xerostomia (bipolar use)
Genitourinary: Azotemia, impotence, renal failure, urinary frequency, urinary retention
Hematologic: Acute intermittent porphyria, agranulocytosis, aplastic anemia, bone marrow suppression, eosinophilia, leukocytosis, leukopenia, pancytopenia, thrombocytopenia
Hepatic: Abnormal liver function tests, hepatic failure, hepatitis, jaundice
Neuromuscular & skeletal: Back pain, pain (bipolar use 12%), peripheral neuritis, weakness
Ocular: Blurred vision, conjunctivitis, lens opacities, nystagmus
Otic: Hyperacusis, tinnitus
Miscellaneous: Diaphoresis, hypersensitivity (including multiorgan reactions, may include disorders mimicking lymphoma, eosinophilia, hepatosplenomegaly, vasculitis); infection (bipolar use 12%)
Postmarketing and/or case reports: Suicidal ideation
Metabolism/Transport Effects
Substrate of CYP2C8 (minor), 3A4 (major); Induces CYP1A2 (strong), 2B6 (strong), 2C8 (strong), 2C9 (strong), 2C19 (strong), 3A4 (strong)
Drug Interactions
Acetaminophen: CarBAMazepine may increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy
Adenosine: CarBAMazepine may enhance the adverse/toxic effect of Adenosine. Specifically, the risk of higher degree heart block may be increased. Management: Consider using a lower initial dose of adenosine in patients who are receiving carbamazepine. Risk D: Consider therapy modification
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Allopurinol: May increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy
Aminocamptothecin: CarBAMazepine may decrease the serum concentration of Aminocamptothecin. Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of CarBAMazepine. Risk C: Monitor therapy
Aripiprazole: CarBAMazepine may decrease the serum concentration of Aripiprazole. Risk D: Consider therapy modification
Bendamustine: CYP1A2 Inducers (Strong) may decrease the serum concentration of Bendamustine. Concentrations of active metabolites may be increased. Risk C: Monitor therapy
Benzodiazepines (metabolized by oxidation): CarBAMazepine may increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Calcium Channel Blockers (Dihydropyridine): CarBAMazepine may increase the metabolism of Calcium Channel Blockers (Dihydropyridine). Exceptions: Clevidipine. Risk C: Monitor therapy
Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of CarBAMazepine. CarBAMazepine may increase the metabolism of Calcium Channel Blockers (Nondihydropyridine). Risk D: Consider therapy modification
Carbonic Anhydrase Inhibitors: May increase the serum concentration of CarBAMazepine. Exceptions: Brinzolamide; Dorzolamide. Risk C: Monitor therapy
Caspofungin: Inducers of Drug Clearance may decrease the serum concentration of Caspofungin. Management: Consider using an increased caspofungin dose of 70mg daily in adults (or 70mg/m2, up to a maximum of 70mg, daily in pediatric patients) when coadministered with known inducers of drug clearance. Risk D: Consider therapy modification
Cimetidine: May increase the serum concentration of CarBAMazepine. The serum carbamazepine concentration might return to normal within one week of starting cimetidine. Risk C: Monitor therapy
ClomiPRAMINE: CarBAMazepine may increase the serum concentration of ClomiPRAMINE. Risk C: Monitor therapy
Clozapine: CarBAMazepine may increase the metabolism of Clozapine. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Contraceptive (Progestins): CarBAMazepine may diminish the therapeutic effect of Contraceptive (Progestins). Contraceptive failure is possible. Risk D: Consider therapy modification
CycloSPORINE: CarBAMazepine may decrease the serum concentration of CycloSPORINE. Risk D: Consider therapy modification
CYP1A2 Substrates: CYP1A2 Inducers (Strong) may increase the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP2B6 Substrates: CYP2B6 Inducers (Strong) may increase the metabolism of CYP2B6 Substrates. Risk C: Monitor therapy
CYP2C19 Substrates: CYP2C19 Inducers (Strong) may increase the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C8 Substrates (High risk): CYP2C8 Inducers (Highly Effective) may increase the metabolism of CYP2C8 Substrates (High risk). Risk C: Monitor therapy
CYP2C9 Substrates (High risk): CYP2C9 Inducers (Highly Effective) may increase the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
CYP3A4 Substrates: CYP3A4 Inducers (Strong) may increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Dabigatran Etexilate: P-Glycoprotein Inducers may decrease the serum concentration of Dabigatran Etexilate. Risk C: Monitor therapy
Danazol: May decrease the metabolism of CarBAMazepine. Risk D: Consider therapy modification
Darunavir: CarBAMazepine may decrease the serum concentration of Darunavir. Risk X: Avoid combination
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Desmopressin: CarBAMazepine may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy
Doxycycline: CarBAMazepine may decrease the serum concentration of Doxycycline. Risk D: Consider therapy modification
Dronedarone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronedarone. Risk X: Avoid combination
Etravirine: CarBAMazepine may decrease the serum concentration of Etravirine. Management: The manufacturer of etravirine states these drugs should not be used in combination. Risk X: Avoid combination
Everolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Everolimus. Management: Everolimus prescribing information recommends avoiding concurrent use of strong CYP3A4 inducers, but if strong CYP3A4 inducers cannot be avoided, consider gradually (in 5mg increments) increasing the everolimus dose from 10mg/day to 20mg/day. Risk X: Avoid combination
Fluconazole: May decrease the metabolism of CarBAMazepine. Risk C: Monitor therapy
Flunarizine: CarBAMazepine may decrease the serum concentration of Flunarizine. Risk C: Monitor therapy
Grapefruit Juice: May decrease the metabolism of CarBAMazepine. Risk C: Monitor therapy
Haloperidol: CarBAMazepine may increase the metabolism of Haloperidol. Risk D: Consider therapy modification
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Irinotecan: CarBAMazepine may decrease the serum concentration of Irinotecan. Concentrations of the active metabolite SN-38 may also be reduced. Management: Change to a non-enzyme inducing anticonvulsant, when clinically possible, at least 2 weeks prior to beginning irinotecan. Dosage increases for irinotecan may be needed when used with carbamazepine, but specific dosing guidelines are not available. Risk D: Consider therapy modification
Isoniazid: May decrease the metabolism of CarBAMazepine. Risk D: Consider therapy modification
Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Lacosamide: CarBAMazepine may decrease the serum concentration of Lacosamide. Risk C: Monitor therapy
LamoTRIgine: May enhance the adverse/toxic effect of CarBAMazepine. CarBAMazepine may increase the metabolism of LamoTRIgine. Risk D: Consider therapy modification
Lithium: CarBAMazepine may enhance the adverse/toxic effect of Lithium. Risk C: Monitor therapy
Macrolide Antibiotics: May decrease the metabolism of CarBAMazepine. Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. Risk D: Consider therapy modification
MAO Inhibitors: CarBAMazepine may enhance the adverse/toxic effect of MAO Inhibitors. Risk X: Avoid combination
Maraviroc: CYP3A4 Inducers (Strong) may decrease the serum concentration of Maraviroc. Management: Maraviroc adult dose should be increased to 600 mg twice daily when used with strong CYP3A4 inducers. This recommendation only applies in the absence of a concurrent strong CYP3A4 inhibitor (e.g., most protease inhibitors). Risk D: Consider therapy modification
Mebendazole: CarBAMazepine may decrease the serum concentration of Mebendazole. Risk D: Consider therapy modification
Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification
Methadone: CarBAMazepine may increase the metabolism of Methadone. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce dosage of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
Methylfolate: May decrease the serum concentration of CarBAMazepine. Risk C: Monitor therapy
Nefazodone: May increase the serum concentration of CarBAMazepine. Also, concentrations of the active CarBAMazepine epoxide metabolite may be reduced. CarBAMazepine may decrease the serum concentration of Nefazodone. Concentrations of active Nefazodone metabolites may also be reduced. Risk X: Avoid combination
Nilotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilotinib. Risk X: Avoid combination
Oral Contraceptive (Estrogens): CarBAMazepine may diminish the therapeutic effect of Oral Contraceptive (Estrogens). Contraceptive failure is possible. Risk D: Consider therapy modification
Paliperidone: CarBAMazepine may decrease the serum concentration of Paliperidone. Risk C: Monitor therapy
P-Glycoprotein Substrates: P-Glycoprotein Inducers may decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phenytoin: CarBAMazepine may increase the metabolism of Phenytoin. Phenytoin may increase the metabolism of CarBAMazepine. CarBAMazepine may decrease the metabolism of Phenytoin. Possibly by competitive inhibition at sites of metabolism. Risk D: Consider therapy modification
Propoxyphene: May decrease the metabolism of CarBAMazepine. Risk D: Consider therapy modification
Protease Inhibitors: CarBAMazepine may increase the metabolism of Protease Inhibitors. Protease Inhibitors may decrease the metabolism of CarBAMazepine. Risk D: Consider therapy modification
Ranolazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ranolazine. Risk X: Avoid combination
Risperidone: CarBAMazepine may decrease the serum concentration of Risperidone. Risk C: Monitor therapy
Rufinamide: May decrease the serum concentration of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Rufinamide. Risk C: Monitor therapy
Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of CarBAMazepine. Specifically those SSRIs that inhibit CYP3A4 isoenzymes. CarBAMazepine may increase the metabolism of Selective Serotonin Reuptake Inhibitors. Specifically those agents metabolized via CYP1A2, 2C, and/or 3A4 isoenzymes. Risk D: Consider therapy modification
Sorafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sorafenib. Risk D: Consider therapy modification
Tadalafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tadalafil. Management: Erectile dysfunction: monitor for decreased effectiveness - no standard dose adjustments recommended. Avoid use of tadalafil for pulmonary arterial hypertension in patients receiving a strong CYP3A4 inducer. Risk D: Consider therapy modification
Temsirolimus: CarBAMazepine may decrease the serum concentration of Temsirolimus. Concentrations of the active metabolite, sirolimus, are also likely to be decreased (and maybe to an even greater degree). Management: Temsirolimus prescribing information recommends against coadministration with strong CYP3A4 inducers such as carbamazepine; however, if concurrent therapy is necessary, an increase in temsirolimus dose to 50 mg/week should be considered. Risk D: Consider therapy modification
Theophylline Derivatives: CarBAMazepine may increase the metabolism of Theophylline Derivatives. Exceptions: Dyphylline. Risk C: Monitor therapy
Thyroid Products: CarBAMazepine may decrease the serum concentration of Thyroid Products. Risk C: Monitor therapy
Tolvaptan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tolvaptan. Management: If concurrent use is necessary, increased doses of tolvaptan (with close monitoring for toxicity and clinical response) may be needed. Risk X: Avoid combination
Topiramate: CarBAMazepine may decrease the serum concentration of Topiramate. Risk D: Consider therapy modification
Treprostinil: CYP2C8 Inducers (Highly Effective) may decrease the serum concentration of Treprostinil. Risk C: Monitor therapy
Tricyclic Antidepressants: CarBAMazepine may increase the metabolism of Tricyclic Antidepressants. Exceptions: ClomiPRAMINE. Risk C: Monitor therapy
Valproic Acid: CarBAMazepine may increase the metabolism of Valproic Acid. Valproic Acid may decrease the serum concentration of CarBAMazepine. Carbamazepine-Epoxide concentrations might increase, offsetting the decreases in the parent compound. Risk C: Monitor therapy
Vecuronium: CarBAMazepine may decrease the serum concentration of Vecuronium. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): CarBAMazepine may decrease the serum concentration of Vitamin K Antagonists. Risk D: Consider therapy modification
Voriconazole: CarBAMazepine may decrease the serum concentration of Voriconazole. Risk X: Avoid combination
Ziprasidone: CarBAMazepine may increase the metabolism of Ziprasidone. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase CNS depression).
Food: Carbamazepine serum levels may be increased if taken with food. Carbamazepine serum concentration may be increased if taken with grapefruit juice; avoid concurrent use.
Herb/Nutraceutical: Avoid evening primrose (seizure threshold decreased). Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
Mechanism of Action
In addition to anticonvulsant effects, carbamazepine has anticholinergic, antineuralgic, antidiuretic, muscle relaxant, antimanic, antidepressive, and antiarrhythmic properties; may depress activity in the nucleus ventralis of the thalamus or decrease synaptic transmission or decrease summation of temporal stimulation leading to neural discharge by limiting influx of sodium ions across cell membrane or other unknown mechanisms; stimulates the release of ADH and potentiates its action in promoting reabsorption of water; chemically related to tricyclic antidepressants
Pharmacodynamics/Kinetics
Absorption: Slow
Distribution: Vd: Neonates: 1.5 L/kg; Children: 1.9 L/kg; Adults: 0.59-2 L/kg
Protein binding: Carbamazepine: 75% to 90%, may be decreased in newborns; Epoxide metabolite: 50%
Metabolism: Hepatic via CYP3A4 to active epoxide metabolite; induces hepatic enzymes to increase metabolism
Bioavailability: 85%
Half-life elimination: Note: Half-life is variable because of autoinduction which is usually complete 3-5 weeks after initiation of a fixed carbamazepine regimen.
Carbamazepine: Initial: 25-65 hours; Extended release: 35-40 hours; Multiple doses: Children: 8-14 hours; Adults: 12-17 hours
Epoxide metabolite: Initial: 25-43 hours
Time to peak, serum: Unpredictable:
Immediate release: Suspension: 1.5 hour; tablet: 4-5 hours
Extended release: Carbatrol®, Equetro®: 12-26 hours (single dose), 4-8 hours (multiple doses); Tegretol®-XR: 3-12 hours
Excretion: Urine 72% (1% to 3% as unchanged drug); feces (28%)
Dosage
Dosage must be adjusted according to patient's response and serum concentrations. Administer tablets (chewable or conventional) in 2-3 divided doses daily and suspension in 4 divided doses daily. Oral:
Epilepsy:
Children:
<6 years: Initial: 10-20 mg/kg/day divided twice or 3 times daily as tablets or 4 times/day as suspension; increase dose every week until optimal response and therapeutic levels are achieved
Maintenance dose: Divide into 3-4 doses daily (tablets or suspension); maximum recommended dose: 35 mg/kg/day
6-12 years: Initial: 200 mg/day in 2 divided doses (tablets or extended release tablets) or 4 divided doses (oral suspension); increase by up to 100 mg/day at weekly intervals using a twice daily regimen of extended release tablets or 3-4 times daily regimen of other formulations until optimal response and therapeutic levels are achieved
Maintenance: Usual: 400-800 mg/day; maximum recommended dose: 1000 mg/day
Note: Children <12 years who receive ?400 mg/day of carbamazepine may be converted to extended release capsules (Carbatrol®) using the same total daily dosage divided twice daily
Children >12 years and Adults: Initial: 400 mg/day in 2 divided doses (tablets or extended release tablets) or 4 divided doses (oral suspension); increase by up to 200 mg/day at weekly intervals using a twice daily regimen of extended release tablets or capsules, or a 3-4 times/day regimen of other formulations until optimal response and therapeutic levels are achieved; usual dose: 800-1200 mg/day
Maximum recommended doses:
Children 12-15 years: 1000 mg/day
Children >15 years: 1200 mg/day
Adults: 1600 mg/day; however, some patients have required up to 1.6-2.4 g/day
Trigeminal or glossopharyngeal neuralgia: Adults: Initial: 200 mg/day in 2 divided doses (tablets, extended release tablets, or extended release capsules) or 4 divided doses (oral suspension) with food, gradually increasing in increments of 200 mg/day as needed
Maintenance: Usual: 400-800 mg daily in 2 divided doses (tablets, extended release tablets, or extended release capsules) or 4 divided doses (oral suspension); maximum dose: 1200 mg/day
Bipolar disorder: Adults: Initial: 400 mg/day in 2 divided doses (tablets, extended release tablets, or extended release capsules) or 4 divided doses (oral suspension), may adjust by 200 mg/day increments; maximum dose: 1600 mg/day.
Note: Equetro® is the only formulation specifically approved by the FDA for the management of bipolar disorder.
Dental Usual Dosing
Trigeminal or glossopharyngeal neuralgia: Oral:
Adults: Initial: 200 mg/day in 2 divided doses (tablets, extended release tablets, or extended release capsules) or 4 divided doses (oral suspension) with food, gradually increasing in increments of 200 mg/day as needed
Maintenance: Usual: 400-800 mg daily in 2 divided doses (tablets, extended release tablets, or extended release capsules) or 4 divided doses (oral suspension); maximum dose: 1200 mg/day
Administration: Oral
Suspension: Must be given on a 3-4 times/day schedule versus tablets which can be given 2-4 times/day. Since a given dose of suspension will produce higher peak and lower trough levels than the same dose given as the tablet form, patients given the suspension should be started on lower doses given more frequently (same total daily dose) and increased slowly to avoid unwanted side effects. When carbamazepine suspension has been combined with chlorpromazine or thioridazine solutions, a precipitate forms which may result in loss of effect. Therefore, it is recommended that the carbamazepine suspension dosage form not be administered at the same time with other liquid medicinal agents or diluents. Should be administered with meals.
Extended release capsule (Carbatrol®, Equetro®): Consists of three different types of beads: Immediate release, extended-release, and enteric release. The bead types are combined in a ratio to allow twice daily dosing. May be opened and contents sprinkled over food such as a teaspoon of applesauce; may be administered with or without food; do not crush or chew.
Extended release tablet: Should be inspected for damage. Damaged extended release tablets (without release portal) should not be administered. Should be administered with meals; swallow whole, do not crush or chew.
Monitoring Parameters
CBC with platelet count, reticulocytes, serum iron, lipid panel, liver function tests, urinalysis, BUN, serum carbamazepine levels, thyroid function tests, serum sodium; pregnancy test; ophthalmic exams (pupillary reflexes); observe patient for excessive sedation, especially when instituting or increasing therapy; signs of rash; HLA-B*1502 genotype screening prior to therapy initiation in patients of Asian descent; suicidality (eg, suicidal thoughts, depression, behavioral changes)
Reference Range
Timing of serum samples: Absorption is slow, peak levels occur 6-8 hours after ingestion of the first dose; the half-life ranges from 8-60 hours, therefore, steady-state is achieved in 2-5 days
Therapeutic levels: 4-12 mcg/mL (SI: 17-51 ?mol/L)
Toxic concentration: >15 mcg/mL; patients who require higher levels of 8-12 mcg/mL (SI: 34-51 ?mol/L) should be watched closely. Side effects including CNS effects occur commonly at higher dosage levels. If other anticonvulsants are given therapeutic range is 4-8 mcg/mL.
Test Interactions
May interact with some pregnancy tests; increased BUN, AST, ALT, bilirubin, alkaline phosphatase (S); decreased calcium, T3, T4, sodium (S)
Dietary Considerations
Drug may cause GI upset, take with large amount of water or food to decrease GI upset. May need to split doses to avoid GI upset.
Patient Education
Take exactly as directed; do not increase dose or frequency or discontinue this medication without consulting prescriber. Do not use extended release tablets which have been damaged or crushed. While using this medication, do not use alcohol and other prescription or OTC medications (especially pain medications, sedatives, antihistamines, or hypnotics) without consulting prescriber. Avoid grapefruit juice. Maintain adequate hydration unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); or nausea, vomiting, loss of appetite, or dry mouth (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). Wear identification of epileptic status and medications. Report CNS changes, suicide ideation, mentation changes, suicidal ideation, depression, or changes in cognition; muscle cramping, weakness, tremors, sore throat, mouth ulcers, swollen glands, fever, jaundice, changes in gait; persistent GI symptoms (cramping, constipation, vomiting, anorexia); rash or skin irritations; unusual bruising or bleeding (mouth, urine, stool); or worsening of seizure activity, or loss of seizure control. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.
Geriatric Considerations
Elderly may have increased risk of SIADH-like syndrome. Elderly are more susceptible to carbamazepine-induced confusion and agitation, AV block, and bradycardia.
Anesthesia and Critical Care Concerns/Other Considerations
Evidence-Based Information: Concurrent use with nondepolarizing Neuromuscular Blocking Agents (NMBAs): Patients on chronic carbamazepine therapy (>7 days) require larger and more frequent doses of nondepolarizing NMBAs to attain the same degree of muscle relaxation. The most likely reason for this reduced sensitivity is increased clearance of the NMBA due to hepatic enzyme induction (Hans, 1997; Richard, 2005; Soriano, 2001).
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Comment
The extended-release capsule (Equetro®) is approved for acute manic and mixed episodes associated with bipolar I disorder. Like valproic acid and lithium, carbamazepine is considered a first-line agent. However, it is a significant inducer of hepatic enzymes. It is a heteroinducer and therefore, induces its own metabolism as well as metabolism of other drugs. Single-dose studies of carbamazepine show half-life ranges of 30-40 hours. After 3 weeks of continuous administration, the half-life decreases to ~20 hours. This reduction is caused by an increase in clearance resulting from autoinduction in metabolism. It is prudent to recheck serum carbamazepine levels after the first month of maintenance therapy. During chronic monotherapy, the half-life is ~12 hours and during polytherapy (with enzyme inducers; eg, phenytoin, phenobarbital), it is reduced to 8 hours. Maximal hepatic activation occurs within 2-4 weeks. Because of this, one has to be vigilant for drug-drug interactions. Studies have failed to document a correlation between plasma levels of carbamazepine and clinical response. However, correlation between CSF levels of carbamazepine's principle metabolite, the 10,11-epoxide, and clinical response in mania and depression have been observed. Therefore, this agent is best dosed clinically. Serum levels >12 mcg/mL do, however, correlate with toxicity. Carbamazepine is also used for a variety of other disorders such as aggressive behavior/episodic dyscontrol, eating disorders, alcohol withdrawal, anxiety disorders, behavioral disturbances in the developmentally disabled, and as an adjunctive agent to antipsychotic for the treatment of psychosis.
Nursing: Physical Assessment/Monitoring
Assess effectiveness and interactions of other medications patient may be taking. Monitor therapeutic effectiveness, laboratory values, and adverse reactions at beginning of therapy and periodically with long-term use. Taper dosage slowly when discontinuing. Observe and teach seizure/safety precautions. Monitor for mental and CNS changes, excessive sedation (especially when initiating or increasing therapy), suicide ideation. Baseline and periodic eye exams (slit lamp, funduscopy, and tonometry) are recommended. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, extended release:
Carbatrol®, Equetro®: 100 mg, 200 mg, 300 mg
Suspension, oral: 100 mg/5 mL (5 mL, 10 mL, 450 mL)
Tegretol®: 100 mg/5 mL (450 mL) [contains propylene glycol; citrus vanilla flavor]
Tablet: 200 mg
Epitol®, Tegretol®: 200 mg
Tablet, chewable: 100 mg
Tegretol®: 100 mg
Tablet, extended release:
Tegretol®-XR: 100 mg, 200 mg, 400 mg
Pricing: U.S. (www.drugstore.com)
Capsule, 12-hour (Carbatrol)
100 mg (30): $60.58
200 mg (60): $106.91
300 mg (60): $108.10
Capsule, 12-hour (Equetro)
100 mg (60): $78.61
200 mg (60): $97.19
300 mg (60): $120.05
Chewable (CarBAMazepine)
100 mg (60): $14.99
Chewable (Tegretol)
100 mg (60): $39.55
Suspension (CarBAMazepine)
100 mg/5 mL (450): $56.84
Suspension (Tegretol)
100 mg/5 mL (450): $58.28
Tablet, 12-hour (TEGretol XR)
100 mg (30): $26.37
200 mg (30): $39.56
400 mg (30): $65.93
Tablets (CarBAMazepine)
200 mg (90): $13.99
Tablets (Tegretol)
200 mg (60): $65.93
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International Brand Names
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Last full review/revision September 2009
Content last modified September 2009
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