Carbamazepine - Drug Monograph

Introduction

Carbamazepine is an iminostilbene derivative anticonvulsant and specific analgesic agent that has been used clinically since the 1960s. It is considered a first-line treatment for partial seizures and trigeminal neuralgia, with additional applications in bipolar disorder management. This drug monograph provides comprehensive information for healthcare professionals regarding the appropriate use, monitoring, and safety considerations of carbamazepine therapy.

Mechanism of Action

Carbamazepine exerts its therapeutic effects primarily through use-dependent blockade of voltage-gated sodium channels. By binding to these channels in their inactive state, carbamazepine stabilizes hyperexcited neural membranes, inhibits repetitive neuronal firing, and reduces synaptic propagation of impulses. Additional mechanisms include modulation of voltage-gated calcium channels, reduction of glutamate release, and potentiation of GABAergic neurotransmission. The drug's exact mechanism in neuropathic pain conditions involves suppression of ectopic neural discharge in damaged nerves.

Indications

FDA-approved indications:

• Partial seizures with complex symptomatology
• Generalized tonic-clonic seizures
• Mixed seizure patterns
• Trigeminal neuralgia

Off-label uses (supported by clinical evidence):

• Bipolar disorder (acute manic/mixed episodes and maintenance)
• Neuropathic pain syndromes
• Alcohol withdrawal syndrome
• Restless legs syndrome

Dosage and Administration

• Epilepsy: Initial dose 200 mg twice daily, increase weekly by 200 mg/day to maintenance dose of 800-1200 mg/day in 3-4 divided doses
• Trigeminal neuralgia: Initial dose 100 mg twice daily, increase by 200 mg/day until pain relief (max 1200 mg/day)
• Bipolar disorder: 400-1600 mg/day in divided doses

• Initial dose 10-20 mg/kg/day in 2-3 divided doses
• Maintenance dose: Increase weekly to maximum of 35 mg/kg/day

• Elderly: Initiate with lower doses due to increased sensitivity
• Hepatic impairment: Reduce dose and monitor carefully
• Renal impairment: Use with caution; may require dose adjustment

• Immediate-release tablets: 100 mg, 200 mg
• Extended-release tablets: 100 mg, 200 mg, 400 mg
• Chewable tablets: 100 mg, 200 mg
• Oral suspension: 100 mg/5 mL

Pharmacokinetics

Contraindications

• History of bone marrow depression
• Hypersensitivity to carbamazepine or tricyclic antidepressants
• Concomitant use with MAO inhibitors (within 14 days)
• Patients with HLA-B*1502 allele (in populations at risk)
• Concomitant use with nefazodone

Warnings and Precautions

• Aplastic anemia and agranulocytosis
• Serious dermatologic reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)
• HLA-B*1502 genetic variant associated with increased risk of serious skin reactions in Asian populations

• Suicidal ideation and behavior
• Hyponatremia and SIADH
• Hepatic effects (hepatitis, hepatic failure)
• Cardiovascular effects (AV block, arrhythmias)
• Ophthalmic effects (diplopia, blurred vision)
• Teratogenicity (neural tube defects)
• Withdrawal seizures if discontinued abruptly

Drug Interactions

• CYP3A4 inhibitors (e.g., erythromycin, fluconazole, verapamil): ↑ carbamazepine levels
• CYP3A4 inducers (e.g., rifampin, phenytoin): ↓ carbamazepine levels
• Oral contraceptives: ↓ efficacy due to induction
• Warfarin: ↓ anticoagulant effect
• Other antiepileptics: complex bidirectional interactions
• Lithium: increased neurotoxic effects

• CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4
• UGT enzymes
• P-glycoprotein

Adverse Effects

• Dizziness
• Drowsiness
• Nausea/vomiting
• Diplopia
• Ataxia

• Hyponatremia
• Rash
• Elevated liver enzymes
• Leukopenia
• Headache

• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Aplastic anemia
• Agranulocytosis
• Hepatitis
• Pancreatitis
• Cardiac conduction abnormalities

Monitoring Parameters

• CBC with differential
• Liver function tests
• Serum electrolytes (sodium)
• Renal function
• Pregnancy test (if applicable)
• HLA-B*1502 screening in high-risk populations

• CBC monthly for first 2-3 months, then quarterly
• LFTs periodically
• Serum sodium levels (especially in elderly)
• Drug levels: therapeutic range 4-12 mcg/mL
• Signs of dermatologic reactions
• Mental status changes
• Ophthalmic examinations

• Trough levels most useful
• Monitor more frequently during dose adjustments
• Consider active metabolite monitoring in special populations

Patient Education

• Take with food to minimize GI upset
• Do not crush or chew extended-release formulations
• Maintain consistent dosing schedule
• Avoid abrupt discontinuation
• Use effective contraception (drug decreases efficacy of hormonal methods)
• Report any skin rash immediately
• Monitor for signs of infection (fever, sore throat)
• Be aware of potential drowsiness; avoid driving until effects known
• Avoid alcohol consumption
• Carry medical identification indicating anticonvulsant use
• Regular blood tests are necessary for safety monitoring
• Report symptoms of hyponatremia (nausea, headache, confusion)

References

1. Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551-563.

2. Wiffen PJ, Derry S, Moore RA, et al. Carbamazepine for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2014;(4):CD005451.

3. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170.

4. Product Information: Tegretol® (carbamazepine). Novartis Pharmaceuticals Corporation.

5. Chen P, Lin JJ, Lu CS, et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med. 2011;364(12):1126-1133.

6. Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49(7):1239-1276.

7. FDA Drug Safety Communication: FDA warns of serious skin reactions with the antiepileptic drug carbamazepine. December 2013.