Tegretol - Drug Monograph

Introduction

Tegretol (carbamazepine) is an anticonvulsant medication first approved by the FDA in 1968. It belongs to the class of iminostilbene derivatives and is structurally related to tricyclic antidepressants. Tegretol is primarily used for the treatment of epilepsy and neuropathic pain, with additional applications in psychiatric disorders. It remains a cornerstone therapy for partial seizures and trigeminal neuralgia despite the introduction of newer antiepileptic drugs.

Mechanism of Action

Carbamazepine exerts its therapeutic effects primarily through use-dependent blockade of voltage-gated sodium channels. By binding to the inactive state of these channels, it stabilizes hyperexcited neuronal membranes, inhibits repetitive neuronal firing, and reduces synaptic impulse propagation. Additional mechanisms include:

• Modulation of voltage-gated calcium channels
• Potentiation of GABAergic inhibition
• Reduction of glutamate release
• Effects on adenylate cyclase and adenosine receptors

The drug's action results in decreased neuronal excitability and suppression of paroxysmal discharges, making it effective for seizure control and pain modulation.

Indications

• Partial seizures with complex symptomatology
• Generalized tonic-clonic seizures
• Mixed seizure patterns
• Trigeminal neuralgia
• Acute manic and mixed episodes in bipolar I disorder

• Diabetic neuropathy
• Postherpetic neuralgia
• Alcohol withdrawal syndrome
• Schizophrenia (adjunctive therapy)
• 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 gradually to 400-800 mg/day
• Bipolar disorder: Initial dose 400-600 mg/day in divided doses, increase to 800-1200 mg/day

• Initial dose 10-20 mg/kg/day in 2-3 divided doses
• Maintenance dose: <6 years: 35-45 mg/kg/day; 6-12 years: 35-40 mg/kg/day; >12 years: 25-35 mg/kg/day

• Geriatric: Start with lowest possible dose
• Renal impairment: Use with caution; consider dose reduction
• Hepatic impairment: Contraindicated in active liver disease
• Pregnancy: Requires careful risk-benefit assessment (Pregnancy Category D)

• Tablets: 200 mg
• Chewable tablets: 100 mg
• Extended-release tablets: 100, 200, 400 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 (or within 14 days)
• Patients with porphyria
• AV conduction abnormalities (unless paced)
• Hepatic disease

Warnings and Precautions

• Aplastic anemia and agranulocytosis
• Serious dermatologic reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Suicidal behavior and ideation

• HLA-B*1502 allele screening in Asian patients (increased risk of SJS/TEN)
• Hyponatremia and SIADH
• Cardiac conduction abnormalities
• Hepatic failure
• Increased intraocular pressure
• Cognitive impairment
• Teratogenicity (neural tube defects)

Drug Interactions

• CYP3A4 inhibitors: clarithromycin, erythromycin, fluconazole, verapamil (increased carbamazepine levels)
• CYP3A4 inducers: rifampin, phenytoin, phenobarbital (decreased carbamazepine levels)
• Oral contraceptives: reduced efficacy
• Warfarin: reduced anticoagulant effect
• Other antiepileptics: complex interactions requiring monitoring
• MAO inhibitors: hypertensive crisis

Adverse Effects

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

• Blood dyscrasias (aplastic anemia, agranulocytosis)
• Severe dermatologic reactions
• Hepatic failure
• Hyponatremia
• Cardiac arrhythmias
• Pancreatitis

Monitoring Parameters

• CBC with differential
• Liver function tests
• Serum electrolytes
• Renal function
• ECG in patients with cardiac risk factors
• Pregnancy test
• HLA-B*1502 screening in high-risk populations

• CBC monthly for first 2-3 months, then quarterly
• Liver function tests periodically
• Serum sodium levels
• Drug levels (therapeutic range 4-12 mcg/mL)
• Signs of dermatologic reactions
• Mood changes and suicidal ideation

Patient Education

• Take with food to minimize GI upset
• Do not crush or chew extended-release formulations
• Avoid grapefruit juice
• Report any skin rash immediately
• Monitor for signs of infection (fever, sore throat)
• Be aware of potential drowsiness; avoid driving until effects known
• Use effective contraception
• Carry medication identification
• Do not abruptly discontinue medication
• Regular follow-up with healthcare provider

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. FDA prescribing information: Tegretol (carbamazepine). Revised 2022.

4. 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.

5. Mula M. The safety of antiepileptic drugs in bipolar disorder. Expert Opin Drug Saf. 2016;15(9):1179-1184.

6. Johannessen Landmark C, Patsalos PN. Drug interactions involving the new second-generation antiepileptic drugs. Expert Rev Neurother. 2010;10(1):119-140.

7. National Institute for Health and Care Excellence. Epilepsies: diagnosis and management. Clinical guideline CG137. 2021.