Carbamazepine

MAO Inhibitor use within last 14 days
Bone Marrow suppression
Pregnancy
Tricyclic compound sensitivity
Asian patients who are positive for HLA-B1502
1. Risk of Steven's Johnson: 5% if HLA-B1502 positive
2. Also associated with Toxic Epidermal Necrolysis
3. FDA has issued a black box warning
4. Man (2007) Epilepsia 48(5):1015-8 [PubMed]

Dibenzazepine Anticonvulsant with chemical structure similar to Tricyclic Antidepressants
Primary anticonvulsant effects
1. Inhibits Neuron depolarization and Glutamate release
2. Sodium Channel Blocker (similar to Eslicarbazepine and Oxcarbazepine)
  1. Binds Sodium channels that are in an inactive state
  2. Decreases Sodium, Calcium and Potassium currents across Neuronal membranes
Other effects
1. Diuretic

Delayed effects after ingestion, peaking at up to 12 hours after ingestion (96 hours for extended release formulations)
Elimination Half-Life: 18 hours
1. Zero order kinetics in Overdose (linear, constant elimination rate regardless of concentration)

Gradual tolerance to side effects (slowly titrate)
Extended release products may be better tolerated (lower peak levels)
Common
1. Headache
2. Lethargy, Fatigue or Somnolence
  1. In the longterm, relatively well tolerated on the spectrum of anticonvulsant related sedation
3. Nausea and Vomiting
Toxicity, Poisoning or Overdose
1. Hypotension
2. Neurologic
  1. Tremor or Myoclonus
  2. Nystagmus
  3. Dizziness
  4. Ataxia or altered coordination
  5. Diplopia (may occur with non-toxic levels)
  6. Seizures
3. Anticholingeric Poisoning
  1. Mydriasis
  2. Skin Flushing
  3. Dry Skin and mucous membranes
  4. Tachycardia
  5. QRS Prolongation

Morbilliform rash
Gingival Hyperplasia
Bone Marrow Suppression with Blood dyscrasias (rarely serious)
1. Agranulocytosis
2. Aplastic Anemia
3. Leukopenia
  1. Mild Leukopenia is most common manifestation
Cardiac conduction abnormality (increases A-V delay)
Hyponatremia (SIADH)
1. Occurs in up to 40% of patients
2. Risk factors include older age, Diuretic use and concurrent Selective Serotonin Reuptake Inhibitor (SSRI) use
Hepatotoxicity or Liver failure (very rare)
Osteoporosis (with longterm use)
Serum Sickness
Life-Threatening Drug-Induced Rashes
1. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome)
2. Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis (TEN)
  1. Most common with asian descent and HLA-B 1502 Mutation (and possibly HLA-B3101)

Contraindicated combinations
1. MAO Inhibitors (may be lethal in combination with Carbamazepine)
Agents that increase Carbamazepine epoxide levels
1. Brivaracetam
2. Felbamate
3. Lamotrigine
4. Valoproic Acid
Agents that have decreased efficacy while taking Carbamazepine
1. Estrogen containing contraceptives
2. Oral Progestin only contraceptives
3. Etonogestrel Implant
Mechanisms
1. Substrate of Cytochrome P450 2C8/9
2. Substrate of Cytochrome P450 3A4
3. Induces Cytochrome P450 1A2
4. Induces Cytochrome P450 2B6
5. Induces Cytochrome P450 2C8/9
6. Induces Cytochrome P450 2C19
7. Induces Cytochrome P450 3A4
8. P-Glycoprotein

Titrate dose to serum concentration and effect
Target serum concentration: 4-12 mcg/ml
1. Observe closely for concentration 8 mcg/ml or higher
Toxic serum concentration: >15 mcg/ml

Seizure Disorder
1. Initial: 200 mg orally twice daily
2. Increase by 200 mg/day increments weekly
  1. Typically up to 800-1200 mg/day (rare use of 1600 mg/day) in divided dosing
3. Target concentration: 4 to 12 mcg/ml
Seizure Disorder (Carnevix IV formulation)
1. IV dose is 70% of oral daily dose divided every 6 hours for patients who are NPO
Trigeminal Neuralgia (FDA approved) or Neuropathic Pain (non-FDA approved)
1. Initial: 100 mg orally twice daily
2. Increase by 100 to 200 mg/day increments weekly as needed for pain management
3. Target: 400 to 800 mg/day divided twice daily
4. Maximum: 1200 mg/day
Bipolar Disorder or Mania
1. Initial: 200 mg orally twice daily
2. Increase by 200 mg as often as every 2 to 4 days in acute mania as tolerated
  1. Slower titration results in fewer side effects
3. Target: 200-1600 mg/day in divided dosing (typical effective dose 1000 mg/day)
  1. Divide dose 3 to 4 times per day (or twice daily if extended release formulation)
4. Maximum: 1600 mg/day in divided dosing
5. Target serum level: 4 to 12 mcg/ml

Seizure Disorder
1. Age >=12 years old: Use adult doses
2. Age 6 to 12 years old
  1. Start 100 mg orally twice daily (or 50 mg suspension orally four times daily)
  2. Increase by 100 mg/day each week divided three to four times daily (or twice daily if extended release) as needed
  3. Maximum: 35 mg/kg/day up to 1000 mg/day in divided doses
3. Age <6 years old
  1. Start 10 to 20 mg/kg/day divided 2 to 3 times daily, increase as needed on weekly basis
  2. Maximum: 35 mg/kg/day
Bipolar Disorder or Mania (age >6 years old, non-FDA approved)
1. Start 100 to 200 mg orally daily to twice daily
2. Increase dose every 2 to 4 days as needed
  1. Typical dose child: 200 to 600 mg/day divided
  2. Typical dose teen: 200 to 1200 mg/day divided

See Adverse Effects above (dose dependent)
Lab Testing and Diagnostics
1. See Unknown Ingestion (includes Serum Glucose, other Toxicology Screening)
2. Serial Serum Carbamazepine levels
3. Electrocardiogram (EKG)
Supportive Care
1. Oral Activated Charcoal in an alert patient if presentation within 1-2 hours of ingestion
2. Whole Bowel Irrigation (and repeat Activated Charcoal) if sustained release Carbamazepine ingestion
3. Hypotension management
  1. Intravenous Fluids
  2. Vasopressors
4. QRS Widening
  1. Sodium Bicarbonate IV ampules until QRS narrows
5. Seizures
6. Hemodialysis Indications
  1. Refractory Seizures
  2. Cardiac Instability
Disposition
1. May discharge home if asymptomatic at 4 to 6 hours after ingestion and decreasing Serum Carbamazepine levels

Routine labs
1. Obtain monthly for first 2 months, then every 3 to 12 months
2. Complete Blood Count with Platelet Count
3. Liver Function Tests
HLA-B1502 (risk of life threatening skin reactions)
1. See contraindications above
2. Indicated before starting in asian and indian patients
3. HLA-B3101 may also be associated with similar skin reactions
Serum Carbamazepine level
1. Initial: Every 1-2 weeks
2. Later: Every 3-6 months
3. Also check before and after dose changes
Other tests previously monitored with Carbamazepine use