How should carbamazepine be prescribed and monitored for a patient with epilepsy or bipolar disorder?

Carbamazepine Prescribing and Monitoring

Carbamazepine should be initiated as monotherapy at low doses (50-100 mg twice daily for adults, 1 mg/kg for children) and titrated slowly over 1-2 weeks to therapeutic blood levels of 4-8 mcg/mL, with mandatory baseline and ongoing monitoring of complete blood count and liver function tests. 1, 2, 3

Initial Prescribing Strategy

Seizure Type Selection

• Prescribe carbamazepine for partial seizures and generalized tonic-clonic seizures only 1, 4
• Do not use for absence seizures (petit mal), as carbamazepine does not control these and may worsen atypical absence seizures 4
• For partial onset seizures, carbamazepine should be preferentially offered to both children and adults 1

Starting Doses

• Adults: Begin with 100 mg twice daily, increasing gradually over 1-2 weeks 2, 3
• Children: Start at 1 mg/kg and titrate to appropriate dosage 1
• For paroxysmal kinesigenic dyskinesia: Initial dose of 50 mg, with most patients achieving complete remission at 50-200 mg/day 1
• Administer in at least two divided doses daily to avoid excessive peak levels that occur with single dosing 3

Critical Pre-Treatment Screening

• Screen for HLA-B*15:02 allele before initiating therapy, particularly in patients of Asian descent (especially Han Chinese), to reduce risk of Stevens-Johnson syndrome 2, 5
• Obtain detailed history focusing on: cardiac conduction abnormalities, hepatic or renal disease, bone marrow disorders, prior hypersensitivity reactions to anticonvulsants or tricyclic antidepressants 4

Therapeutic Drug Monitoring

Target Levels and Timing

• Maintain therapeutic blood levels between 4-8 mcg/mL 2
• Draw blood samples 4-6 days after each dose adjustment to avoid falsely elevated results from transient changes 2, 5
• Once seizures are controlled, measure plasma levels to establish optimum individual patient levels 3

Dose Titration

• Increase doses slowly as tolerated, monitoring for side effects including fatigue, dizziness, ataxia, double vision, nausea, and vomiting 3
• 65% of patients experience at least one adverse event (versus 27% on placebo), though most are dose-dependent and transient 2
• If dizziness is problematic, consider bedtime dosing to minimize daytime effects 2

Laboratory Monitoring Protocol

Baseline Testing

• Complete blood count 2
• Liver function tests 2
• HLA-B*15:02 screening (Asian patients) 2, 5

Ongoing Monitoring Schedule

• Monthly liver function tests for the first 3 months, then every 3-6 months if stable 2
• Regular complete blood count monitoring throughout treatment 2
• More frequent monitoring required for patients with pre-existing liver disease 2

Critical Monitoring Pitfalls to Avoid

• Do not draw carbamazepine levels too soon after dosing, as this leads to falsely elevated results 2
• Do not overlook drug interactions when adjusting monitoring frequency 2
• Watch for persistent elevation of liver enzymes, which may require discontinuation 2

Hematologic Monitoring

Leukopenia Management

• Leukopenia may be transient or persistent and requires careful monitoring but is not cause for immediate discontinuation 3
• Monitor more closely during first 3-4 months when aplastic anemia risk is highest 3

Aplastic Anemia Risk

• Aplastic anemia is rare but potentially fatal, occurring as an idiosyncratic, non-dose-related reaction most likely within the first 3-4 months 3
• Educate patients to report fever, sore throat, rash, mouth ulcers, easy bruising, lymphadenopathy, or petechial/purpuric hemorrhage immediately 4

Critical Drug Interactions

Medications That Increase Carbamazepine Levels (Risk of Toxicity)

• Isoniazid can increase carbamazepine levels, potentially leading to toxicity 2, 6
• Macrolide antibiotics, metronidazole, verapamil, diltiazem, cimetidine, and certain antidepressants inhibit metabolism 6

Medications Decreased by Carbamazepine

• Carbamazepine significantly decreases levels of oral contraceptives, warfarin, and corticosteroids through hepatic enzyme induction 2, 6
• Women using oral contraceptives must be advised of reduced effectiveness and consider alternative contraception 2, 4
• Also reduces levels of other anticonvulsants (valproic acid, lamotrigine, topiramate), cyclosporin, theophylline, and chemotherapeutic agents 6

Medications That Decrease Carbamazepine Levels

• Phenytoin, phenobarbital, and primidone accelerate elimination by stimulating CYP3A4 6

Special Populations

Women of Childbearing Age

• Control seizures with monotherapy at minimum effective dose 1
• Prescribe folic acid routinely when on carbamazepine 1
• Counsel about reduced oral contraceptive effectiveness 2, 4
• If pregnancy occurs, register with North American Antiepileptic Drug Pregnancy Registry (1-888-233-2334) 4
• Standard breastfeeding recommendations remain appropriate, though carbamazepine passes into breast milk 1, 4

Patients with Intellectual Disability

• Consider carbamazepine instead of phenytoin or phenobarbital due to lower risk of behavioral adverse effects 1

Bipolar Disorder

• Carbamazepine (or lithium/valproate) should be offered for acute mania 1
• Typical doses range 400-1600 mg/day with serum concentrations of 8-12 mcg/mL for psychiatric indications 7
• Useful alone or in combination with lithium, particularly in patients intolerant of or unresponsive to lithium 7

Discontinuation Protocol

When to Consider Stopping

• Discontinuation should be considered after 2 seizure-free years 1
• Decision must involve patient and family, considering clinical, social, and personal factors 1

Tapering Schedule

• Taper gradually over 2-4 weeks to minimize withdrawal risks including seizure recurrence 8
• Never discontinue abruptly, as this significantly increases seizure risk and may cause status epilepticus 8, 4
• If withdrawal symptoms occur or seizures recur, re-escalate to last effective dose and attempt slower taper 8

Monitoring During Taper

• Assess for seizure activity at each dose reduction 8
• Monitor for withdrawal symptoms 8
• Watch for re-emergence of original condition 8
• Do not rush taper in patients with poorly controlled seizures or those on high doses 8

Serious Adverse Effects Requiring Immediate Action

Dermatologic Reactions

• Serious skin reactions including Stevens-Johnson syndrome can occur; patients must consult physician immediately if skin reaction develops 4
• Risk highest in HLA-B*15:02 positive patients 2, 5

Hepatic Effects

• Range from slight enzyme elevations to rare hepatic failure 4
• Hepatic effects may progress despite discontinuation 4
• Symptoms include jaundice, dark urine, right upper quadrant pain, easy bruising, anorexia, nausea/vomiting 4

Cardiac Effects

• Second- and third-degree AV heart block have been reported, particularly in patients with underlying EKG abnormalities 4
• Symptoms include fast/slow/pounding heartbeat, shortness of breath, lightheadedness, fainting 4

Neurologic Toxicity

• Carbamazepine toxicity can mimic cerebrovascular accidents with focal neurological deficits, even at prescribed doses 9
• Severe toxicity may cause cardiovascular instability, intractable seizures, and coma 9

Contraindications

Do not prescribe carbamazepine if patient has: 4

• History of bone marrow depression
• Allergy to carbamazepine or tricyclic antidepressants
• Current use of nefazodone
• MAOI use within last 14 days