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

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

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

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)

  • 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

Pediatric

Obstetric and Fetal

  • As mentioned above, carbamazepine is teratogenic!

Medically Ill

Resources

References

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.