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Sunday, July 27, 2025

Carbamazepine


Carbamazepine is a widely used antiepileptic and mood-stabilizing drug indicated for the treatment of several neurologic and psychiatric conditions. Originally introduced in the 1960s, it remains a cornerstone therapy for focal seizures, trigeminal neuralgia, and bipolar disorder. It is chemically classified as a dibenzazepine derivative, structurally related to tricyclic antidepressants, and exerts its action by stabilizing hyperexcited neuronal membranes and inhibiting repetitive neuronal firing.

This professional monograph provides a comprehensive overview of carbamazepine, detailing its mechanisms of action, approved uses, dosing strategies, pharmacokinetics, contraindications, adverse effects, precautions, drug interactions, and considerations for pregnancy and specific populations.

Pharmacological Classification

  • Therapeutic class: Anticonvulsant, mood stabilizer, neuropathic pain modulator

  • Pharmacologic class: Dibenzazepine derivative

  • ATC code: N03AF01

  • US FDA Classification: Rx only

Brand Names and Formulations

  • Tegretol®, Carbatrol®, Equetro®, Tegretol Retard®, Epitol®, Finlepsin®, Timonil®

  • Available forms:

    • Immediate-release tablets: 100 mg, 200 mg

    • Extended-release (ER) tablets/capsules: 100 mg, 200 mg, 400 mg

    • Oral suspension: 100 mg/5 mL

    • Chewable tablets: 100 mg

    • Rectal suppositories (rare in practice)

Mechanism of Action

Carbamazepine acts primarily by blocking voltage-gated sodium channels in neuronal membranes, prolonging their inactive state. This results in:

  • Inhibition of sustained high-frequency neuronal firing

  • Reduction in synaptic transmission, especially in hyperexcitable cortical neurons

  • Stabilization of neuronal membranes

In bipolar disorder, the precise mechanism is not fully elucidated, but carbamazepine likely modulates neurotransmitter release and second messenger systems affecting mood stabilization. It also reduces polysynaptic responses and presynaptic propagation of excitatory impulses.

Indications

Approved (UK, EU, FDA)

  • Epilepsy

    • Focal seizures (with or without secondary generalization)

    • Generalized tonic-clonic seizures

    • Mixed seizure types (excluding absence seizures)

  • Trigeminal neuralgia

    • First-line agent for idiopathic or secondary causes

  • Glossopharyngeal neuralgia

  • Bipolar disorder

    • Acute manic or mixed episodes (FDA approval for Equetro® in bipolar I disorder)

  • Diabetic neuropathy (off-label in some guidelines)

  • Alcohol withdrawal syndrome (off-label in certain protocols)

Dosage and Administration

Adults (Epilepsy)

  • Initial: 100–200 mg once or twice daily

  • Titration: Increase gradually by 100–200 mg every 2–3 days

  • Maintenance: 800–1200 mg/day in 2–3 divided doses

  • Maximum: Up to 1600–2000 mg/day in resistant cases

Trigeminal Neuralgia

  • Start: 100 mg twice daily

  • Increase: 100 mg every 12 hours until pain relief (typical dose 400–800 mg/day)

  • Maximum: 1200 mg/day

Bipolar Disorder (Equetro®)

  • Initial: 200 mg twice daily

  • Increase: In 200 mg increments per day

  • Target range: 800–1200 mg/day

  • Therapeutic plasma concentration: 4–12 mcg/mL

Children (Epilepsy)

  • <6 years: Start with 10–20 mg/kg/day

  • ≥6 years: Begin at 100 mg/day; titrate weekly

  • Maintenance: Based on weight and clinical response

Administration Notes

  • Take with food to reduce GI irritation

  • ER formulations should not be crushed or chewed

  • Plasma monitoring advised for dose optimization and toxicity avoidance

Pharmacokinetics

  • Absorption: Slow, variable; improved with food

  • Bioavailability: ~70–80%

  • Time to peak: 4–8 hours (IR); 12–24 hours (ER)

  • Protein binding: 70–80%

  • Metabolism: Hepatic (CYP3A4, CYP2C8) to active epoxide metabolite

  • Half-life:

    • Initial: 25–65 hours (decreases with autoinduction)

    • Maintenance: ~12–17 hours

  • Excretion: Primarily renal as metabolites

Contraindications

  • Hypersensitivity to carbamazepine or tricyclic antidepressants

  • History of bone marrow depression

  • Concomitant use of monoamine oxidase inhibitors (MAOIs)

    • Must wait ≥14 days after stopping MAOI therapy

  • Use with delavirdine or other NNRTIs due to reduced efficacy

  • History of hepatic porphyrias (acute intermittent, variegate, mixed)

Warnings and Precautions

  • Serious dermatologic reactions

    • Stevens-Johnson Syndrome (SJS)

    • Toxic Epidermal Necrolysis (TEN)

    • Strong association with HLA-B*15:02 allele (common in Asian descent); genetic screening recommended

  • Aplastic anemia and agranulocytosis

    • Rare but life-threatening; baseline and periodic blood counts required

  • Hyponatremia/SIADH

    • Especially in elderly or when used with diuretics

  • Hepatotoxicity

    • Monitor LFTs periodically

  • Suicidality

    • Antiepileptic drugs may increase risk of suicidal ideation or behavior

  • Withdrawal seizures

    • Avoid abrupt discontinuation

Adverse Effects

Common (>1%)

  • CNS: Drowsiness, dizziness, ataxia, headache, diplopia, blurred vision, nystagmus

  • GI: Nausea, vomiting, dry mouth, constipation

  • Dermatologic: Rash, pruritus

  • Hematologic: Leukopenia (usually benign and transient)

  • Others: Edema, weight gain, fatigue

Serious (Rare)

  • SJS/TEN

  • Aplastic anemia, agranulocytosis, thrombocytopenia

  • Hepatitis, cholestatic jaundice

  • Cardiac arrhythmia, AV block (especially in overdose)

  • Pancreatitis

  • Multi-organ hypersensitivity syndrome

Drug Interactions

Inducer of CYP450 enzymes (especially CYP3A4) → multiple interactions

Reduces efficacy of:

  • Oral contraceptives (may cause breakthrough bleeding)

  • Warfarin, cyclosporine, theophylline, antivirals, doxycycline

Levels increased by:

  • Erythromycin, clarithromycin

  • Isoniazid, verapamil, diltiazem, fluoxetine

Levels reduced by:

  • Phenytoin, phenobarbital, primidone, rifampicin

Additive toxicity with:

  • Lithium: Neurotoxicity risk

  • CNS depressants: Enhanced sedation

  • MAOIs: Contraindicated

Pregnancy and Lactation

Pregnancy Category D (UK/US)

  • Known teratogen

  • Risks:

    • Neural tube defects (e.g., spina bifida)

    • Craniofacial abnormalities

    • Cardiac defects

    • Developmental delay

  • Folate supplementation recommended

  • Use in pregnancy only if benefits outweigh risks; often considered if seizures are life-threatening

Lactation

  • Carbamazepine is excreted in breast milk

  • Breastfeeding may be permitted with infant monitoring for drowsiness, poor feeding, hepatic dysfunction

Monitoring Parameters

  • Baseline and periodic labs:

    • Full blood count (FBC)

    • Liver function tests (LFTs)

    • Renal function

    • Serum sodium

    • Plasma carbamazepine levels (target: 4–12 mcg/mL)

  • Genetic screening:

    • HLA-B*15:02 in Asian patients

    • HLA-A*31:01 in European populations (SJS/TEN risk)

  • Suicidal thoughts or behavior monitoring

  • Signs of toxicity: CNS depression, cardiac arrhythmia, severe skin reactions

Patient Counseling Points

  • Take with food to reduce stomach upset

  • Do not crush or chew extended-release tablets

  • Report rash, sore throat, fever, easy bruising, yellowing of the skin, or vision changes

  • Avoid alcohol and CNS depressants

  • Use effective contraception; hormonal methods may be less effective

  • Do not discontinue abruptly

  • Attend regular blood tests and clinic visits for monitoring




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