Carbamazepine (Tegretol)

Primer

Carbamazepine (Trade name: Tegretol) is a mood stabilizer and antiepileptic used in the treatment of epilepsy and bipolar disorder. It is used in the treatment of acute mania and mixed episodes of bipolar I disorder.

Pharmacokinetics

See also article: Introduction to Pharmacology

Pharmacokinetics of Carbamazepine

Absorption	Absorption is relatively slow, but peak plasma levels are reached within 2 hours
Distribution	Highly protein bound (70 to 80%)
Metabolism	Liver, primarily by CYP 3A4
Elimination	30% renally eliminated
Half-life	35 hours

See also article: Cytochrome (CYP) P450 Metabolism

Carbamazepine: Cytochrome P450 Metabolism

Substrate of (Metabolized by)	3A4 (autoinduces and potent!)
Induces	3A4 (autoinduces and potent!)
Inhibits

Pharmacodynamics

Mechanism of Action

Blocks α subunit of VSNaC
Blocks Na+ channels
?possible actions on K and Ca channels

Toxicity

At toxic levels, there can be neurotoxicity
- Dose dependent effects: diplopia, drowsiness, blurred vision, cognitive impairment

Indications

Trigeminal neuralgia
Bipolar disorder
Behavioural and psychological symptoms of dementia

Dosing

Dosing for Carbamazepine

Starting	Start at 100 mg BID (it is usually dosed BID)
Titration	100 mg every 2-3 days as tolerated, up to an initial target dose of at least 300 mg/day. After at least 5 days at this target dose (to allow steady state), a carbamazepine trough level should be drawn 12 hours after the last dose.
Maximum	1200mg
Taper

The dose range for carbamazepine is between 100- (using the CR formulation), and it is usually dosed BID.

Serum Levels

Carbamazepine Levels

<17 μmol/L	Dose should be increased by 100 mg/day and another level should be drawn in 5 days
17-54 μmol/L	Dose can be maintained
>54 μmol/L	Dose should be reduced by 100 mg/day and another level should be drawn in 5 days

Note that carbamazepine induces its own metabolism. Thus, drawing levels repeatedly for the same dose will be necessary over the first few weeks, making dose adjustments as necessary.

Remember that unlike lithium levels, the carbamazepine level correlates poorly with therapeutic and clinical effect.
The purpose of drawing levels is to ensure there is no toxicity.

Formulations

Carbamazepine comes in oral formulation.

Monitoring

Since carbamazepine is its own substrate for CYP 3A4 metabolism (autoinduction), you must monitor blood level weekly for the first 8 weeks of treatment.
Serum level monitoring should also be done every 6 to 12 months to ensure that serum levels are not in the toxic range.
- Signs of high levels of carbamazepine include diplopia, poor coordination, and sedation.
Carbamazepine is highly protein bound, and thus albumin levels should be measured.

Contraindications

Absolute

Relative

Drug-Drug Interactions

Carbamazepine is a strong inducer of CYP3A4 and P-glycoprotein (P-gp) and it induces substrates of CYP 1A2, 3A4, 2C9, 2B6.
- Thus it can induce (“chew up”) many psychotropic medications that are typically metabolized by most CYP enzymes, leading to very low levels of those medications.

Side Effects

Carbamazepine has many drug-drug interactions, and can cause more side effects in the elderly.
Weight gain, transaminitis, SIADH, blood dyscrasias, AV node delays, bradycardia.
Sedation, dizziness, fatigue, nausea, leukopenia (low white blood cell count) in up to 7%
Hypersensitivity rashes and reactions are uncommon
- In older adults, some concerns have been raised about bone marrow suppression as well for hypersensitivity

Adverse Events

Agranulocytosis

Agranulocytosis or aplastic anemia (1/10,000 to 1/125,000)
- Monitor for fever, bruising, petechiae

Hepatotoxicity

GGT increases is common but hepatotoxicity is rare

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

See main article: Pharmacogenetic Testing

Han Chinese or Asian ethnicity patients should have genotyping performed prior to starting carbamazepine to ensure that they do not have the HLA-B*1502, which confers a significant risk for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
Northern European ancestry individuals may also be at increased risk if they have the HLA-A*3101 allele.^[1]

Teratogen

Carbamazepine is teratogenic and can cause neural tube defects^[2]
- Increased risk for cleft lip/palate, and spina bifida

Clinical Pearls

It is very important to tell all patients who take carbamazepine to report to their physician any and all skin rashes and/or mouth sores that develop.

Special Populations

Geriatric

See main article: Geriatric Pharmacology

Pediatric

See main article: Pediatric Pharmacology

Obstetric and Fetal

See main article: Obstetric and Fetal Pharmacology

As mentioned above, carbamazepine is teratogenic!

Medically Ill

See main article: Psychotropic Dosing in the Medically Ill

Resources

¹⁾ McCormack, M., Alfirevic, A., Bourgeois, S., Farrell, J. J., Kasperavičiūtė, D., Carrington, M., ... & Pirmohamed, M. (2011). HLA-A* 3101 and carbamazepine-induced hypersensitivity reactions in Europeans. New England Journal of Medicine, 364(12), 1134-1143.

²⁾ Matlow, J., & Koren, G. (2012). Is carbamazepine safe to take during pregnancy?. Canadian Family Physician, 58(2), 163-164.

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