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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.
Pronunciation
(kar ba MAZ e peen)
Generic Available (U.S.)
Yes
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Carbatrol®: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM241639.pdf
Equetro®: http://www.equetro.com/pdfs/Equetro-Medication-Guide.pdf
TEGretol®, TEGretol®-XR: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM246796.pdf
REMS Components
Equetro®: Released from REMS requirement 1/27/2012
Carbatrol®: Released from REMS requirement 8/22/2011
Tegretol®, Tegretol®-XR: Released from REMS requirement 10/30/2011
Brand Names: U.S.
Brand Names: Canada
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
Treatment of restless leg syndrome and post-traumatic stress disorders
Pregnancy Risk Factor
D
Pregnancy Considerations
Studies in pregnant women have demonstrated a risk to the fetus; therefore, the manufacturer classifies carbamazepine as pregnancy category D. Carbamazepine and its metabolites can be found in the fetus. Carbamazepine may be associated with teratogenic effects, including spina bifida, craniofacial defects, cardiovascular malformations, and hypospadias. The risk of teratogenic effects is higher with anticonvulsant polytherapy than monotherapy.Developmental delays have also been observed following in utero exposure to carbamazepine (per manufacturer); however, socioeconomic factors, maternal and paternal IQ, and polytherapy may contribute to these findings. Pregnancy may cause small decreases of carbamazepine plasma concentrations in the second and third trimesters; monitoring should be considered. When used for the treatment of bipolar disorder, use of carbamazepine should be avoided during the first trimester of pregnancy if possible. The use of a single medication for the treatment of bipolar disorder or epilepsy in pregnancy is preferred. Carbamazepine may decrease plasma concentrations of hormonal contraceptives; breakthrough bleeding or unintended pregnancy may occur and alternate or back-up 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”; AAP 2001 update pending)
Breast-Feeding Considerations
Carbamazepine and its active epoxide metabolite are found in breast milk. Carbamazepine can also be detected in the serum of nursing infants. Transient hepatic dysfunction has been observed in some case reports. Nursing should be discontinued if adverse events are observed. According to the manufacturer, the decision to continue or discontinue breast-feeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother. Respiratory depression, seizures, nausea, vomiting, diarrhea, and/or decreased feeding have been observed in neonates exposed to carbamazepine in utero and may represent a neonatal withdrawal syndrome.
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.
• Asian ancestry: 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: Use caution in elderly patients; may cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults (Beers Criteria). May also 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), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP1A2 (strong), CYP2B6 (strong), CYP2C19 (strong), CYP2C8 (strong), CYP2C9 (strong), CYP3A4 (strong), P-glycoprotein
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
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of CarBAMazepine. Risk C: Monitor therapy
ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double aripiprazole dose when initiating concomitant therapy with a CYP3A4 inducer (e.g., carbamazepine). Monitor response and adjust aripiprazole dose as clinically indicated. If CYP3A4 inducer is discontinued, reduce aripiprazole dose to 10-15 mg/day. Risk D: Consider therapy modification
Axitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Axitinib. Risk X: Avoid combination
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
Boceprevir: CarBAMazepine may decrease the serum concentration of Boceprevir. Risk X: Avoid combination
Bortezomib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bortezomib. Risk X: Avoid combination
Brentuximab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Risk C: Monitor therapy
Calcium Channel Blockers (Dihydropyridine): CarBAMazepine may increase the metabolism of Calcium Channel Blockers (Dihydropyridine). Management: Consider calcium channel blocker (CCB) dose adjustments or alternative therapy in patients receiving concomitant carbamazepine. Nimodipine Canadian labeling contraindicates concurrent use with carbamazepine. Exceptions: Clevidipine. Risk D: Consider therapy modification
Calcium Channel Blockers (Nondihydropyridine): CarBAMazepine may decrease the serum concentration of Calcium Channel Blockers (Nondihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of CarBAMazepine. Management: Consider empiric reductions in carbamazepine dose with initiation of nondihydropyridine calcium channel blockers. Monitor for increased toxic effects of carbamazepine and reduced therapeutic effects of the calcium channel blocker. 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 70 mg daily in adults (or 70 mg/m2, up to a maximum of 70 mg, 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: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for agranulocytosis may be increased. Risk X: Avoid combination
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. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
Contraceptives (Estrogens): CarBAMazepine may diminish the therapeutic effect of Contraceptives (Estrogens). Contraceptive failure is possible. Management: Use of a nonhormonal contraceptive is recommended. Risk D: Consider therapy modification
Contraceptives (Progestins): CarBAMazepine may diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. Risk D: Consider therapy modification
CycloSPORINE: CarBAMazepine may decrease the serum concentration of CycloSPORINE. Risk D: Consider therapy modification
CycloSPORINE (Systemic): CarBAMazepine may decrease the serum concentration of CycloSPORINE (Systemic). 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: CYP2C8 Inducers (Strong) may increase the metabolism of CYP2C8 Substrates. Risk C: Monitor therapy
CYP2C9 Substrates: CYP2C9 Inducers (Strong) may increase the metabolism of CYP2C9 Substrates. 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/ABCB1 Inducers may decrease the serum concentration of Dabigatran Etexilate. Management: Avoid concurrent use of dabigatran with p-glycoprotein inducers when possible. Closely monitor for decreased levels/effects of dabigatran if concomitantly administering p-glycoprotein inducers, particularly strong inducers. Risk X: Avoid combination
Danazol: May decrease the metabolism of CarBAMazepine. Risk D: Consider therapy modification
Darunavir: May increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy
Dasatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasatinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing dasatinib dose and monitor clinical response and toxicity closely. Risk D: Consider therapy modification
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
Diclofenac: CYP2C9 Inducers (Strong) may decrease the serum concentration of Diclofenac. Risk C: Monitor therapy
Divalproex: CarBAMazepine may increase the metabolism of Divalproex. Divalproex may decrease the serum concentration of CarBAMazepine. Carbamazepine-Epoxide concentrations might increase, offsetting the decreases in the parent compound. 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
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
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
Exemestane: CYP3A4 Inducers (Strong) may decrease the serum concentration of Exemestane. Management: Exemestane prescribing information recommends using an increased dose (50 mg/day) in patients receiving concurrent strong CYP3A4 inducers. Monitor patients closely for evidence of toxicity and/or inadequate clinical response. Risk D: Consider therapy modification
Felbamate: CarBAMazepine may decrease the serum concentration of Felbamate. Felbamate may decrease the serum concentration of CarBAMazepine. Management: In patients receiving carbamazepine, initiate felbamate at 1200 mg/day in divided doses 3-4 times daily while reducing carbamazepine dose by 20%. Monitor for reduced concentrations/effects of both drugs. Risk D: Consider therapy modification
Fluconazole: May decrease the metabolism of CarBAMazepine. Risk C: Monitor therapy
Flunarizine: CarBAMazepine may decrease the serum concentration of Flunarizine. Risk C: Monitor therapy
Fosphenytoin: CarBAMazepine may decrease the serum concentration of Fosphenytoin. CarBAMazepine may increase the serum concentration of Fosphenytoin. Possibly by competitive inhibition at sites of metabolism. Fosphenytoin may decrease the serum concentration of CarBAMazepine. Risk D: Consider therapy modification
Gefitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gefitinib. Management: In the absence of severe adverse drug reactions, consider increasing gefitinib dose to 500 mg daily in patients receiving strong CYP3A4 inducers. Carefully monitor clinical response and development of adverse reactions. Risk D: Consider therapy modification
Grapefruit Juice: May decrease the metabolism of CarBAMazepine. Risk C: Monitor therapy
GuanFACINE: CYP3A4 Inducers (Strong) may decrease the serum concentration of GuanFACINE. Management: Consider increasing the guanfacine dose (within the labeled dosage range) when such a combination is used. Risk D: Consider therapy modification
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
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. 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
Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Ixabepilone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixabepilone. Management: Avoid this combination whenever possible. If this combination must be used, a gradual increase in ixabepilone dose from 40 mg/m2 to 60 mg/m2 (given as a 4-hour infusion), as tolerated, should be considered. Risk D: Consider therapy modification
Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Ketorolac (Nasal): May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Ketorolac (Systemic): 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
Linagliptin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Linagliptin. Management: Strongly consider using an alternative to any strong P-glycoprotein inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Risk D: Consider therapy modification
Lithium: CarBAMazepine may enhance the adverse/toxic effect of Lithium. Risk C: Monitor therapy
Lopinavir: CarBAMazepine may decrease the serum concentration of Lopinavir. Management: Increased doses of lopinavir may be necessary when using these agents in combination. Do not use a once daily lopinavir/ritonavir regimen together with carbamazepine. Increase monitoring of therapeutic response in all patients using this combination. Risk D: Consider therapy modification
Lurasidone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lurasidone. Risk X: Avoid combination
Macrolide Antibiotics: May decrease the metabolism of CarBAMazepine. Exceptions: Azithromycin; Azithromycin (Systemic); Fidaxomicin; 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: Increase maraviroc adult dose to 600 mg twice daily when used with strong CYP3A4 inducers. This does not apply to patients also receiving strong CYP3A4 inhibitors. Do not use maraviroc with strong CYP3A4 inducers in patients with Clcr less than 30 mL/min. Risk D: Consider therapy modification
Mebendazole: CarBAMazepine may decrease the serum concentration of Mebendazole. Risk C: Monitor therapy
Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. 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 adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
Methylfolate: May decrease the serum concentration of CarBAMazepine. Risk C: Monitor therapy
MethylPREDNISolone: CarBAMazepine may decrease the serum concentration of MethylPREDNISolone. Management: Consider an alternative corticosteroid. If this combination cannot be avoided, monitor for diminished methylprednisolone effects during carbamazepine treatment, and increased methylprednisolone effects following carbamazepine discontinuation. Risk D: Consider therapy modification
Metyrosine: CNS Depressants may enhance the sedative effect of Metyrosine. Risk C: Monitor therapy
Mifepristone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mifepristone. Risk X: Avoid combination
Mifepristone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Risk D: Consider therapy modification
Nefazodone: CarBAMazepine may decrease the serum concentration of Nefazodone. Concentrations of active Nefazodone metabolites may also be reduced. Nefazodone may increase the serum concentration of CarBAMazepine. Also, concentrations of the active CarBAMazepine epoxide metabolite may be reduced. Risk X: Avoid combination
Nilotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilotinib. Risk X: Avoid combination
Paliperidone: CarBAMazepine may decrease the serum concentration of Paliperidone. Risk C: Monitor therapy
P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of P-glycoprotein/ABCB1 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 decrease the serum concentration of Phenytoin. CarBAMazepine may increase the serum concentration of Phenytoin. Possibly by competitive inhibition at sites of metabolism. Phenytoin may decrease the serum concentration of CarBAMazepine. Risk D: Consider therapy modification
Praziquantel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Praziquantel. Management: Avoid concomitant use of praziquantel with strong CYP3A4 inducers. Discontinue rifampin 4 weeks prior to initiation of praziquantel therapy. Rifampin may be resumed the day following praziquantel completion. Risk X: Avoid combination
Protease Inhibitors: CarBAMazepine may increase the metabolism of Protease Inhibitors. Protease Inhibitors may decrease the metabolism of CarBAMazepine. Risk D: Consider therapy modification
QuiNINE: CarBAMazepine may decrease the serum concentration of QuiNINE. QuiNINE may increase the serum concentration of CarBAMazepine. Risk D: Consider therapy modification
Rilpivirine: CarBAMazepine may decrease the serum concentration of Rilpivirine. Risk X: Avoid combination
RisperiDONE: CarBAMazepine may decrease the serum concentration of RisperiDONE. Risk C: Monitor therapy
Roflumilast: CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast. Management: Roflumilast U.S. prescribing information recommends against combining strong CYP3A4 inducers with roflumilast. The Canadian product monograph makes no such recommendation but notes that such agents may reduce roflumilast therapeutic effects. Risk X: Avoid combination
Rufinamide: CarBAMazepine may decrease the serum concentration of Rufinamide. Rufinamide may decrease the serum concentration of CarBAMazepine. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: CarBAMazepine may increase the metabolism of Selective Serotonin Reuptake Inhibitors. Specifically those agents metabolized via CYP1A2, 2C, and/or 3A4 isoenzymes. Selective Serotonin Reuptake Inhibitors may decrease the metabolism of CarBAMazepine. Specifically those SSRIs that inhibit CYP3A4 isoenzymes. Risk D: Consider therapy modification
SORAfenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SORAfenib. Risk X: Avoid combination
SUNItinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing sunitinib dose and monitor clinical response and toxicity closely. 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
Telaprevir: CarBAMazepine may decrease the serum concentration of Telaprevir. Telaprevir may increase the serum concentration of CarBAMazepine. Risk X: Avoid combination
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 adult dose to 50 mg/week should be considered. Risk D: Consider therapy modification
Theophylline Derivatives: May decrease the serum concentration of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Risk C: Monitor therapy
Thiazide Diuretics: May enhance the adverse/toxic effect of CarBAMazepine. Specifically, there may be an increased risk for hyponatremia. Risk C: Monitor therapy
Thyroid Products: CarBAMazepine may decrease the serum concentration of Thyroid Products. Risk C: Monitor therapy
Ticagrelor: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ticagrelor. Risk X: Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Topiramate: CarBAMazepine may decrease the serum concentration of Topiramate. Risk D: Consider therapy modification
Toremifene: CYP3A4 Inducers (Strong) may decrease the serum concentration of Toremifene. Risk X: Avoid combination
Treprostinil: CYP2C8 Inducers (Strong) 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
Ulipristal: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ulipristal. 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
Vandetanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vandetanib. Risk X: Avoid combination
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 decrease the serum concentration of Ziprasidone. Risk C: Monitor therapy
Zolpidem: May enhance the CNS depressant effect of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Zolpidem. Risk C: Monitor therapy
Zuclopenthixol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zuclopenthixol. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Ethanol may increase CNS depression. Management: Avoid concurrent use of ethanol.
Food: Carbamazepine serum levels may be increased if taken with food and/or grapefruit juice. Management Avoid concurrent ingestion of grapefruit juice. Maintain adequate hydration, unless instructed to restrict fluid intake.
Herb/Nutraceutical: Evening primrose may decrease seizure threshold. Valerian, St John's wort, kava kava, and gotu kola may increase CNS depression. Management: Avoid evening primrose. Avoid valerian, St John's wort, kava kava, and gotu kola.
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.
Dosing adjustment in renal impairment: Dosage adjustments are not required or recommended in the manufacturer's labeling; however, the following guidelines have been used by some clinicians (Aronoff, 2007):
Children and Adults:
GFR <10 mL/minute: Administer 75% of dose
Hemodialysis, peritoneal dialysis: Administer 75% of dose
Continuous renal replacement therapy (CRRT):
Children: Administer 75% of dose
Adults: No dosage adjustment recommended
Dosing adjustment in hepatic impairment: Use with caution in hepatic impairment; metabolized primarily in the liver
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 micromole/L)
Toxic concentration: >15 mcg/mL; patients who require higher levels of 8-12 mcg/mL (SI: 34-51 micromole/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 cause false-positive serum TCA screen; may interact with some pregnancy tests
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
Do not use extended release tablets which have been damaged or crushed. While using this medication, do not use alcohol. Maintain adequate hydration, unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, blurred vision, nausea, vomiting, loss of appetite, or dry mouth. Wear identification of epileptic status and medications. Report CNS changes, suicide ideation, mentation changes, depression, 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.
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.
This medication is considered to be potentially inappropriate in this patient population (Beers Criteria: Quality of evidence - moderate; Strength of recommendation - strong).
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
Taper dosage slowly when discontinuing. Teach patient safety and seizure precautions. Monitor for mental and CNS changes, excessive sedation (especially when initiating or increasing therapy), and suicide ideation. Baseline and periodic eye exams (slit lamp, funduscopy, and tonometry) are recommended.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, extended release, oral: 100 mg, 200 mg, 300 mg
Carbatrol®: 100 mg, 200 mg, 300 mg
Equetro®: 100 mg, 200 mg, 300 mg
Suspension, oral: 100 mg/5 mL (5 mL, 10 mL, 450 mL)
Tablet, oral: 200 mg
Epitol®: 200 mg [scored]
TEGretol®: 200 mg [scored]
Tablet, chewable, oral: 100 mg
TEGretol®: 100 mg [scored]
Tablet, extended release, oral: 200 mg, 400 mg
TEGretol®-XR: 100 mg, 200 mg, 400 mg
Pricing: U.S. (www.drugstore.com)
Capsule, 12-hour (Carbatrol)
100 mg (30): $65.99
200 mg (60): $118.99
300 mg (60): $115.99
Capsule, 12-hour (Equetro)
200 mg (60): $117.99
300 mg (60): $148.75
Chewable (CarBAMazepine)
100 mg (60): $14.99
Chewable (TEGretol)
100 mg (60): $41.85
Suspension (CarBAMazepine)
100 mg/5 mL (450): $67.95
Suspension (TEGretol)
100 mg/5 mL (450): $81.99
Tablet, 12-hour (CarBAMazepine)
200 mg (100): $86.65
400 mg (100): $175.99
Tablet, 12-hour (TEGretol XR)
100 mg (30): $30.99
200 mg (30): $42.99
400 mg (30): $77.99
Tablets (CarBAMazepine)
200 mg (90): $14.99
Tablets (TEGretol)
200 mg (30): $43.99
Extemporaneously Prepared
Note: Commercial oral suspension is available (20 mg/mL)
A 40 mg/mL oral suspension may be made with tablets. Crush twenty 200 mg tablets in a mortar and reduce to a fine powder. Add small portions of Simple Syrup, NF and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 100 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add sufficient quantity of vehicle to make 100 mL. Label "shake well" and "refrigerate". Stable for 90 days.
Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.
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International Brand Names
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Last full review/revision April 2012
Content last modified April 2012
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