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carbamazepine; CBZ (Tegretol, Atretol, Eiptol, Carbatrol, Equetro)

Tradename: Tegretol, Atretol, Epitol, Carbatrol, Equetro. Indications: 1) prophylactic management of seizures, epilepsy a) partial seizures b) mixed partial seizure disorder 2) bipolar disorder (Equetro) [11], mania 3) attention-deficit hyperactivity disorder (ADHD) [14] 4) trigeminal neuralgia 5) diabetic neuropathy 6) neurogenic pain syndromes 7) alcohol abuse 8) cocaine abuse Contraindications: 1) patients with bone marrow depression 2) concurrent use of monoamine oxidase inhibitors 3) hypersensitivity to tricyclic antidepressants 4) avoid in patients with liver failure [4] 5) less well tolerated in the elderly [4] 6) not advisable in pregnancy [16] Dosage: 1) epilepsy a) start 100-200 mg PO BID with meals b) increase daily dose by 200 weekly c) average effective dose 600-1600 mg QD divided TID/QID 2) neurogenic pain a) start 100 mg PO BID b) increase by 100-200 mg/day weekly Tabs: 100 & 200 mg. Suspension: 100 mg/5 mL. Extended-release (Carbatrol, Tegratol XR, Equetro): - 400-1600 mg divided BID Carbatrol: 200 mg, 300 mg. Equetro: 100, 200, 300 mg. [11] Tegretol XR: 100 mg, 200 mg, 400 mg. * the appropriate dose of anticonvulsant is that dose that prevents seizures with no symptoms of adverse effects - supratherapeutic levels & mild hyponatremia are not symptoms of adverse effects - continue current dose [18] Dosage adjustment in renal failure: - none - supplemental dose after dialysis not required [4] Pharmacokinetics: 1) oral absorption is slow & erratic 2) metabolized in the liver by cyt P450 3A4 (CYP3A4) to active metabolites, including carbamazepine 10,11-epoxide 3) carbamazepine induces cyt P450 3A4: autoinduction of metabolism 4) 1/2 life changes due to auto-induction which changes in 1-2 weeks 5) 1/2 life is 30 hours after 1st dose, 14 hours after 1-2 months 6) 1/2 life of carbamazepine 10,11-epoxide is 17 hours; may accumulate with renal insufficiency 7) anticonvulsant effect varies from hours to days 8) stable therapeutic level may require a month to achieve 9) relief for trigeminal neuralgia occurs in 8-72 hours 10) anti-manic response is generally within 7-10 days Monitor: - HLA-B*1502 allele testing before starting carbamazepine in Asians (Han Chinese & Thai) (see HLA-B*1502 allele) - liver function tests baseline & every 6 months [7] - complete blood count (CBC) baseline, monthly for 2 or 3 months, then at least every other year [7] - serum creatinine, BUN baseline, then periodically [7] - urinalyis baseline, then periodically [7] - serum Na+ periodically (SIADH) - every 2 weeks for 1st 2 months, then every 3 months [15] Adverse effects: 1) Neurologic: - ataxia*, dizziness*, diplopia, vertigo, sedation, fatigue, blurred vision*, slurred speech, nystagmus*, confusion*, peripheral neuropathy 2) gastrointestinal - nausea/vomiting*, GI irritation, hepatotoxicity, diarrhea, hepatitis 3) hematologic: - bone marrow suppression (aplastic anemia), neutropenia*, agranulocytosis, eosinophilia, leukopenia, thrombocytopenia, pancytopenia * mild asymptomatic neutropenia is best observed & monitored [18] 4) skin - rash, Stevens-Johnson syndrome, toxic epidermal necrolysis more common in patients with HLA-B*1502 [12] - drug rash with eosinophilia & systemic symptoms (DRESS) [4] 5) cardiovascular - arrhythmias, AV block, bradycardia, CHF, edema, hypertension, hypotension, syncope - hypercholesterolemia [4] 6) metabolic a) hyponatremia with water intoxication (SIADH) b) hypocalcemia [10] c) decreased bone mineral density [10], osteoporosis [4] 7) genitourinary - urinary retention, sexual problems in males 8) modest teratogenic potential [6] - associated with low birth weight & small for gestational age [16] 9) increased risk of Parkinson's disease (RR~1.8) [17] - association less strong than for lamotrigine, levetiracetam & valproate [17] * common (> 10%) Overdose: treated with activated charcoal & hemoperfusion Drug interactions: 1) carbamazepine levels are decreased by: a) phenobarbital b) phenytoin c) primidone 2) carbamazepine levels are increased by: a) cimetidine b) erythromycin c) verapamil d) clarithromycin e) fluoxetine f) diltiazem g) isoniazid h) propoxyphene 2) carbamazepine increases the metabolism of: a) warfarin b) cyclosporine c) oral contraceptives d) phenytoin [3] e) theophylline f) thyroid hormones g) haloperidol h) doxycycline i) benzodiazepines j) ethosuximide k) valproic acid l) felbamate m) corticosteroids 3) carbamazepine increases phenytoin level [4] 4) valproate may increase active metabolite of carbamazepine (10,11-epoxide) 5) felbamate decreases carbamazepine levels & increases level of active metabolite carbamazepine epoxide 6) carbamazepine induces cyt CYP1A2, CYP2C9 & CYP3A4 thus may diminish levels of drugs metabolized by these cyt P450's 7) any drug that inhibits cyt CYP3A4 may increase levels of carbamazepine 8) any drug that induces cyt CYP3A4, including carbamazepine itself, may diminish levels of carbamazepine 9) carbamazepine inactivates many forms of hormonal contraceptives [4] Laboratory: 1) specimen: a) serum, plasma (EDTA) b) collect at trough concentration c) avoid hemolysis, especially with EIA assay d) stable at room temperature for several hours e) stable for 1 year at -20 degrees C 2) methods: HPLC, GLC, GC-MS, EIA, FPIA, FIA 3) assay generally does not measure active metabolite (10,11- epoxide) Mechanism of action: 1) sodium channel blocker 2) diminishes release of excitatory neurotransmitters 3) decreases synaptic transmission 4) structurally related to tricyclic anti-depressants

Interactions

drug interactions drug adverse effects (more general classes) monitor with anticonvulsants

Related

carbamazepine in serum/plasma cytochrome p450 1A2 (cytochrome P3-450, phenacetin deethylase, cytochrome p450-4, CYP1A2) cytochrome P450 2C9; cytochrome P450 BP-1; cytochrome P450 MP-4; S-mephenytoin-4-hydroxylase; limonene 6-monooxygenase; limonene 7-monooxygenase (CYP2C9, CYP2C10) cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

Specific

carbamazepine 10,11-epoxide

General

anticonvulsant dibenzazepine; iminostilbene mood stabilizer

Properties

MISC-INFO: elimination route LIVER KIDNEY 1/2life 8-20 HOURS 24-26 protein-binding 60-80% therapeutic-range 4-12 UG/ML elimination by hemodialysis - pregnancy-category C safety in lactation ?

Database Correlations

PUBCHEM cid=2554

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 700
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Medical Knowledge Self Assessment Program (MKSAP) 11, 16, 17, 18. American College of Physicians, Philadelphia 1998, 2012, 2015, 2018. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  5. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  6. Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
  7. Prescriber's Letter 8(8):48, 2001
  8. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  9. UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
  10. Prescriber's Letter 10(1):4 2003
  11. Prescriber's Letter 12(2): 2005 Equetro: Extended-Release Carbamazepine Detail-Document#: 210204 (subscription needed) http://www.prescribersletter.com
  12. FDA MedWatch http://www.fda.gov/medwatch/safety/2007/safety07.htm#carbamazepine
  13. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  14. Deprecated Reference
  15. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  16. Kirkner RM Three Antiseizure Medications Join List for Newborn Risks. Medscape. Dec 13, 2022 https://www.medscape.com/viewarticle/985504
  17. Kneisel K Epilepsy Drugs May Up Risk of Parkinson's. Strongest association seen for sodium valproate. MedPage Today December 27, 2022 https://www.medpagetoday.com/neurology/seizures/102398 - Belete D, Jacobs BM, Simonet C et al Association Between Antiepileptic Drugs and Incident Parkinson Disease in the UK Biobank. JAMA Neurol. Published online December 27, 2022. PMID: 36574240 https://jamanetwork.com/journals/jamaneurology/fullarticle/2799620
  18. NEJM Knowledge+ Hematology

Component-of

carbamazepine/lamotrigine/phenobarbital/phenytoin/primidone/valproic acid