Usual Adult Dose for Epilepsy

Immediate-Release:
Initial dose: Tablets: 200 mg orally twice a day
Initial dose: Oral suspension: 100 mg orally 4 times a day

• Increase weekly in increments up to 200 mg per day (as equally divided doses 3 or 4 times a day) until an optimal response is obtained

Maintenance dose: 800 to 1200 mg per day
Maximum dose: 1600 mg per day

Extended-release:
Initial dose: 200 mg orally 2 times a day

• Increase weekly in increments of 200 mg per day as equally divided doses twice a day until an optimal response is obtained

Maximum dose: 1600 mg per day

SWITCHING FROM Immediate-release to Extended-release:

• Provide the same total daily mg dose in equally divided doses twice a day; following conversion, monitor closely for seizure control; depending on response, may need to adjust therapy.

SWITCHING to Oral Suspension:

• Provide the same total daily mg dose but increase the frequency to 3 or 4 times a day

COADMINISTRATION WITH OTHER ANTIEPILEPTIC DRUGS:

• When adding to existing antiepileptic therapy, add gradually while the dose of the concomitant antiepileptic is maintained or gradually decreased

Comments:

• Maintenance dose should be the minimum effective dose, generally 800 to 1200 mg per day.
• Drug level monitoring may be useful for dose selection, minimizing toxicity, verifying drug compliance and assisting with drug interaction monitoring; consider monitoring plasma levels when starting and stopping medications that may alter the metabolism of this drug.
• Absence seizures (petit mal) do not appear to be controlled with this drug; use has been associated with increased frequency of generalized convulsions.

Use: For the treatment of partial seizures with complex symptomatology (psychomotor, temporal lobe), generalized tonic-clonic seizures (grand mal), and mixed seizure patterns which include the above, or other partial or generalized seizures.

Usual Adult Dose for Trigeminal Neuralgia

Immediate-release:
Initial dose: Tablets: 100 mg orally 2 times a day
Initial dose: Oral suspension: 50 mg orally 4 times a day

• Increase by up to 200 mg per day in divided doses to achieve freedom from pain

Maintenance dose: 400 to 800 mg per day
Maximum dose: 1200 mg per day

Extended-release:
Initial dose: 200 mg orally once a day or 100 mg orally every 12 hours

• Increase by up to 200 mg per day in increments of 100 mg every 12 hours to achieve freedom from pain

Maintenance dose: 400 to 800 mg per day
Maximum dose: 1200 mg per day

Comments:

• Maintenance doses in some patients may be 200 mg per day while others may require up to 1200 mg per day; at least once every 3 months, an attempt should be made to reduce, or possibly discontinue therapy, to ensure the minimal effective dose is being used.
• There have been beneficial results reported treating glossopharyngeal neuralgia.
• This drug should not be used to treat trivial aches and pains.

Use: For the treatment of pain associated with true trigeminal neuralgia.

Usual Adult Dose for Mania

Extended-release capsules (Equetro[R]):
Initial dose: 200 mg orally twice a day

• Increase by 200 mg per day to achieve optimal response

Maximum dose: 1600 mg per day

Comments:

• Doses higher than 1600 mg per day have not been studied in mania associated with bipolar disorder.

Use: For the treatment of acute manic or mixed episodes associated with bipolar disorder.

Usual Adult Dose for Bipolar Disorder

Extended-release capsules (Equetro[R]):
Initial dose: 200 mg orally twice a day

• Increase by 200 mg per day to achieve optimal response

Maximum dose: 1600 mg per day

Comments:

• Doses higher than 1600 mg per day have not been studied in mania associated with bipolar disorder.

Use: For the treatment of acute manic or mixed episodes associated with bipolar disorder.

Usual Pediatric Dose for Epilepsy

Less than 6 years of age:
Initial dose: 10 to 20 mg/kg/day orally in 2 to 3 divided doses (immediate-release [IR] tablets), 4 divided doses (oral suspension), OR every 12 hours (extended-release capsules)

• Increase dose at weekly intervals (maintain divided doses) to achieve optimal clinical response
• Maximum dose: 35 mg/kg/day

6 to 12 years of age:
Initial dose: IR tablets or extended-release tablets or capsules: 100 mg orally twice a day
Initial dose: Oral suspension: 100 mg orally 4 times a day

• Increase dose weekly in increments up to 100 mg per day (maintain divided doses) until an optimal response is obtained

Maintenance dose: 400 to 800 mg/day
Maximum dose: 1000 mg per day

Over 12 years:
Initial dose: IR tablets: 200 mg orally twice a day
Initial dose: Oral suspension: 100 mg orally 4 times a day

• Increase weekly in increments up to 200 mg per day (maintain divided doses) until an optimal response is obtained

Maintenance dose: 800 to 1200 mg per day
Maximum dose: 1000 mg per day (12 to 15 years); 1200 mg per day (greater than 15 years)

Extended-release tablets or capsules:
Initial dose: 200 mg orally twice a day

• Increase weekly in increments of 200 mg/day (divided twice a day) until an optimal response is obtained

Maximum dose: 1000 mg per day (12 to 15 years); 1200 mg per day (greater than 15 years)

SWITCHING FROM Immediate-release to Extended-release:

• Provide the same total daily mg dose in equally divided doses twice a day; following conversion, monitor closely for seizure control; depending on response, may need to adjust therapy.

SWITCHING TO ORAL SUSPENSION:

• Provide the same total daily mg dose but increase the frequency to 3 or 4 times a day

COADMINISTRATION WITH OTHER ANTIEPILEPTIC DRUGS:

• When adding to existing antiepileptic therapy, add gradually while the dose of the concomitant antiepileptic is maintained or gradually decreased (phenytoin may need to be increased).

Comments:

• If satisfactory response not achieved, measure plasma levels to determine if within therapeutic range.
• Maintenance dose should be the minimum effective level.
• Drug level monitoring may be useful for dose selection, minimizing toxicity, verifying drug compliance and assisting with drug interaction monitoring; consider monitoring plasma levels when starting and stopping medications that may alter the metabolism of this drug.
• Absence seizures (petit mal) do not appear to be controlled with this drug; use has been associated with increased frequency of generalized convulsions.

Use: For the treatment of partial seizures with complex symptomatology (psychomotor, temporal lobe), generalized tonic-clonic seizures (grand mal), and mixed seizure patterns which include the above, or other partial or generalized seizures.

Renal Dose Adjustments

Use with caution

Liver Dose Adjustments

• Use with caution; lower initial doses of oral suspension are recommended since the oral suspension provides higher peak levels; titrate slowly to avoid unwanted side effects
• Avoid use in patients with a history of hepatic porphyria (acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda)

Discontinue therapy for newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage; or in the case of active liver disease

Dose Adjustments

This drug should be provided in divided doses:

• Immediate-release tablets: Take in divided doses several times a day
• Extended-release tablets or capsules: Take in divided doses twice a day
• Oral liquid: Take in divided doses 2 or 3 times a day

Since different formulations vary in bioavailability and to avoid reduced effect, risk of breakthrough seizures, or excessive side effects, monitor closely if formulation changes are needed as dose adjustment may need to be necessary.

• Switching to Prolonged-Release Tablets: the same total daily dose will generally be suitable. In a few patients, it may be necessary to increase the total daily dose, particularly when it is used with other antiepileptics

Therapeutic drug monitoring/range:
Usual Therapeutic Range: 4 to 12 mcg/mL (17 to 50 micromol/L)

• Monitoring of blood levels may be particularly useful in cases of dramatic increase in seizure frequency; during pregnancy; when treating children or adolescents; in suspected absorption disorders; for verification of compliance; in suspected toxicity where more than one drug is being used

Precautions

US BOXED WARNINGS: SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE

• Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS), have been reported. These reactions are estimated to occur in 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. The risk in some Asian countries is estimated to be about 10 times higher. Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA-B gene. HLA-B*1502 is found almost exclusively in patients with ancestry across broad areas of Asia. Patients with ancestry in genetically at-risk populations should be screened for the presence of HLA-B*1502 prior to drug initiation; patients testing positive for the allele should not be treated with this drug unless the benefit clearly outweighs the risk.

APLASTIC ANEMIA AND AGRANULOCYTOSIS have been reported in association with use of this drug.

• Data from a population-based case control study demonstrate that the risk of developing these reactions is 5 to 8 times greater than in the general population. However, the overall risk of these reactions in the untreated general population is low; approximately 6 patients per 1 million population per year for agranulocytosis and 2 patients per 1 million population per year for aplastic anemia.
• Although reports of transient or persistent decreased platelet or white blood cell counts are not uncommon with use of this drug, data are not available to accurately estimate the incidence or outcome. The vast majority of cases of leukopenia have not progressed to the more serious conditions of aplastic anemia or agranulocytosis.
• Because of the very low incidence of agranulocytosis and aplastic anemia, the vast majority of minor hematologic changes observed in monitoring of patients on this drug are unlikely to signal the occurrence of either abnormality. Nonetheless, complete pretreatment hematologic testing should be obtained as a baseline. If a patient, during treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops.

NARROW THERAPEUTIC INDEX:

• This drug should be considered a narrow therapeutic index (NTI) drug as small differences in dose or blood concentrations may lead to serious therapeutic failures or adverse drug reactions.

Recommendations:

• Generic substitution should be done cautiously, if at all, as current bioequivalence standards are generally insufficient for NTI drugs.
• Additional and/or more frequent monitoring should be done to ensure receipt of an effective dose while avoiding unnecessary toxicities.

CONTRAINDICATIONS:

• Previous bone marrow depression
• Hypersensitivity to this drug or any tricyclic compounds (e.g. amitriptyline, desipramine, imipramine, protriptyline, and nortriptyline)
• Concomitant use, or within 14 days of monoamine oxidase inhibitors (MAOIs)
• Concomitant use of delavirdine or other nonnucleoside reverse transcriptase inhibitors that are substrates for CYP450 3A4
• Concomitant use of nefazodone

Safety and efficacy of the extended-release capsules have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

This drug is slightly dialyzed by hemodialysis. The dialysis clearance averages 54 mL/min. Using a Cobe Century II hollow tube dialyzer with a cuprophane membrane, 10% of a dose is removed during 4 hour of hemodialysis.

Hemoperfusion has been reported to be useful in the removal of carbamazepine during acute overdose.

Other Comments

Administration advice:
Take orally with food

• Oral Suspension: Shake well before measuring; do not mix with other liquid medications or diluents as a precipitate may form
• Extended-Release Tablet: Swallow whole; do not crush, chew, or break tablets; tablet coating is not absorbed and is excreted in the feces (the coating may be noticeable in stool)
• Extended-Release Capsule: Swallow whole or open and sprinkle beads over food, such as a teaspoon of applesauce; do not crush or chew capsules or beads

Storage requirements:

• Protect from light and moisture

General:

• Biomarker information is included in the black box warning, specifically because of an association between the presence of HLA-B*1502 allele and risk for serious dermatologic reactions, high-resolution HLA-B*1502 genotype testing is recommended in genetically at-risk patients. Testing should be performed prior to therapy since over 90% of patients who experience Stevens-Johnson syndrome (SJS) or Toxic Epidermal Necrolysis (TEN) do so within the first few months of therapy.
• The presence of the HLA-A*3101 allele has shown a moderate association between risk of developing hypersensitivity reactions including SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
• Ancestry is an important determinant for identifying at-risk populations; HLA-B*1502 is found almost exclusively in patients with ancestry across broad areas of Asia and largely absent in individuals not of Asian origin (e.g. Caucasians, African-Americans, Hispanics, and Native Americans). HLA-A*3101 is expected to be carried by more than 15% of Japanese, Native America, Southern Indian, and some Arabic ancestry; up to 10% of patients of Han Chinese, Korean, European, Latin American, and other Indian ancestry, and up to about 5% in African Americans and patients of Thai, Taiwanese, and Chinese (Hong Kong) ancestry.
• While the science of pharmacogenomics evolves, appropriate clinical vigilance and patient management is necessary due to the potential for serious adverse reactions.

Monitoring:

• For genetically at-risk patients: High-resolution HLA-B*1502 genotype test prior to starting therapy
• HEMATOLOGIC: Baseline complete blood counts, including platelets, possibly reticulocytes, and serum iron; repeat if patients develops low or decreased WBCs or any signs or symptoms of bone marrow depression
• HEPATIC: Liver function tests at baseline and periodically, especially in patients with a history of liver disease
• RENAL: Baseline and periodic urinalysis and BUN determinations
• OCULAR: Baseline and periodic eye exam
• THERAPEUTIC DRUG MONITORING: Useful for minimizing toxicity and verifying compliance

Patient advice:

• Patients should understand that this drug should not be stopped abruptly.
• Patients should be instructed to immediately report development of any skin reaction or hypersensitivity reaction.
• Patients should be instructed to contact their healthcare provider promptly if they develop signs or symptoms of bone marrow depression, hyponatremia, or any new or unusual reactions.
• Patients should be instructed to discuss all medication changes with their healthcare provider including herbal preparations and over the counter medications; patients should be advised to avoid grapefruit juice, alcohol, and other drugs that may cause sleepiness or dizziness until they speak with their healthcare provider.
• Patients should be informed that this drug may increase the risk of suicidal thinking and behavior and they should immediately report any change in mood or behavior, or the emergence of suicidal thoughts or thoughts about self-harm.
• Women of childbearing potential should understand that this drug may cause fetal harm; they should understand that this drug may decrease the effectiveness of oral contraceptives which may cause contraceptive failure or breakthrough bleeding; if they are pregnant or intend to become pregnant they should speak with their healthcare provider; a pregnancy registry may be found at http://www.aedpregnancyregistry.org/
• Patients should be advised not to drive or operate machinery during therapy until they have discussed this with their healthcare provider.