Carbamazepine

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Carbamazepine is typically used for the treatment of seizure disorders and neuropathic pain. It is used off-label as a second-line treatment for bipolar disorder and in combination with an antipsychotic in some cases of schizophrenia when treatment with a conventional antipsychotic alone has failed.{{cite journal | vauthors = Ceron-Litvoc D, Soares BG, Geddes J, Litvoc J, de Lima MS | title = Comparison of carbamazepine and lithium in treatment of bipolar disorder: a systematic review of randomized controlled trials | journal = Human Psychopharmacology | volume = 24 | issue = 1 | pages = 19–28 | date = January 2009 | pmid = 19053079 | doi = 10.1002/hup.990 | s2cid = 5684931 }} However, evidence does not support its usage for schizophrenia.{{cite journal | vauthors = Leucht S, Helfer B, Dold M, Kissling W, McGrath J | title = Carbamazepine for schizophrenia | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD001258 | date = May 2014 | volume = 2014 | pmid = 24789267 | pmc = 7032545 | doi = 10.1002/14651858.CD001258.pub3 | collaboration = Cochrane Schizophrenia Group }} It is not effective for absence seizures or myoclonic seizures. Although carbamazepine may have a similar effectiveness (as measured by people continuing to use a medication) and efficacy (as measured by the medicine reducing seizure recurrence and improving remission) when compared to phenytoin and valproate, choice of medication should be evaluated on an individual basis as further research is needed to determine which medication is most helpful for people with newly-onset seizures.

In the United States, carbamazepine is indicated for the treatment of epilepsy (including partial seizures, generalized tonic-clonic seizures and mixed seizures), and trigeminal neuralgia. Carbamazepine is the only medication that is approved by the Food and Drug Administration for the treatment of trigeminal neuralgia.{{Cite journal| vauthors = Pino MA |date=19 January 2017 |title= Trigeminal Neuralgia: A "Lightning Bolt" of Pain|url=https://www.uspharmacist.com/article/trigeminal-neuralgia-a-lightning-bolt-of-pain|journal=US Pharmacist|volume=42|pages=41–44}}

As of 2014, a controlled release formulation was available for which there is tentative evidence showing fewer side effects and unclear evidence with regard to whether there is a difference in efficacy.{{cite journal | vauthors = Powell G, Saunders M, Rigby A, Marson AG | title = Immediate-release versus controlled-release carbamazepine in the treatment of epilepsy | journal = The Cochrane Database of Systematic Reviews | volume = 12 | pages = CD007124 | date = December 2016 | issue = 4 | pmid = 27933615 | pmc = 6463840 | doi = 10.1002/14651858.CD007124.pub5 }}

It has also been shown to improve symptoms of "typewriter tinnitus", a type of tinnitus caused by the neurovascular compression of the cochleovestibular nerve. Sunwoo, W., Jeon, Y., Bae, Y. et al. Typewriter tinnitus revisited: The typical symptoms and the initial response to carbamazepine are the most reliable diagnostic clues. Sci Rep 7, 10615 (2017). https://doi.org/10.1038/s41598-017-10798-w

In the US, the label for carbamazepine contains warnings concerning:

• effects on the body's production of red blood cells, white blood cells, and platelets: rarely, there are major effects of aplastic anemia and agranulocytosis reported and more commonly, there are minor changes such as decreased white blood cell or platelet counts, but these do not progress to more serious problems.{{cite web|title=Carbamazepine Drug Label|url=http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7a1e523a-b377-43dc-b231-7591c4c888ea|url-status=live|archive-url=https://web.archive.org/web/20141208063739/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7a1e523a-b377-43dc-b231-7591c4c888ea|archive-date=8 December 2014}}
• increased risks of suicide{{cite journal | vauthors = Vukovic Cvetkovic V, Jensen RH | title = Neurostimulation for the treatment of chronic migraine and cluster headache | journal = Acta Neurologica Scandinavica | volume = 139 | issue = 1 | pages = 4–17 | date = January 2019 | pmid = 30291633 | doi = 10.1111/ane.13034 | s2cid = 52923061 | doi-access = free }}
• increased risks of hyponatremia and SIADH{{cite journal | vauthors = Gandelman MS | s2cid = 36758508 | title = Review of carbamazepine-induced hyponatremia | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 18 | issue = 2 | pages = 211–33 | date = March 1994 | pmid = 8208974 | doi = 10.1016/0278-5846(94)90055-8 }}
• risk of seizures, if the person stops taking the drug abruptly
• risks to the fetus in women who are pregnant, specifically congenital malformations like spina bifida, and developmental disorders.{{cite journal | vauthors = Jentink J, Dolk H, Loane MA, Morris JK, Wellesley D, Garne E, de Jong-van den Berg L | title = Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study | journal = BMJ | volume = 341 | pages = c6581 | date = December 2010 | pmid = 21127116 | pmc = 2996546 | doi = 10.1136/bmj.c6581 }}
• Pancreatitis
• Hepatitis
• Dizziness
• Bone marrow suppression
• Stevens–Johnson syndrome

Common adverse effects may include drowsiness, dizziness, headaches and migraines, ataxia, nausea, vomiting, and/or constipation. Alcohol use while taking carbamazepine may lead to enhanced depression of the central nervous system. Less common side effects may include increased risk of seizures in people with mixed seizure disorders,{{cite journal | vauthors = Liu L, Zheng T, Morris MJ, Wallengren C, Clarke AL, Reid CA, Petrou S, O'Brien TJ | s2cid = 7693614 | title = The mechanism of carbamazepine aggravation of absence seizures | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 319 | issue = 2 | pages = 790–8 | date = November 2006 | pmid = 16895979 | doi = 10.1124/jpet.106.104968 }} abnormal heart rhythms, blurry or double vision. Also, rare case reports of an auditory side effect have been made, whereby patients perceive sounds about a semitone lower than previously; this unusual side effect is usually not noticed by most people, and disappears after the person stops taking carbamazepine.{{cite journal | vauthors = Tateno A, Sawada K, Takahashi I, Hujiwara Y | title = Carbamazepine-induced transient auditory pitch-perception deficit | journal = Pediatric Neurology | volume = 35 | issue = 2 | pages = 131–4 | date = August 2006 | pmid = 16876011 | doi = 10.1016/j.pediatrneurol.2006.01.011 }}

Serious skin reactions such as Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) due to carbamazepine therapy are more common in people with a particular human leukocyte antigen gene-variant (allele), HLA-B*1502. Odds ratios for the development of SJS or TEN in people who carry the allele can be in the double, triple or even quadruple digits, depending on the population studied.{{cite journal | vauthors = Kaniwa N, Saito Y | title = Pharmacogenomics of severe cutaneous adverse reactions and drug-induced liver injury | journal = Journal of Human Genetics | volume = 58 | issue = 6 | pages = 317–26 | date = June 2013 | pmid = 23635947 | doi = 10.1038/jhg.2013.37 | doi-access = free }}{{cite journal | vauthors = Amstutz U, Shear NH, Rieder MJ, Hwang S, Fung V, Nakamura H, Connolly MB, Ito S, Carleton BC | title = Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions | journal = Epilepsia | volume = 55 | issue = 4 | pages = 496–506 | date = April 2014 | pmid = 24597466 | doi = 10.1111/epi.12564 | hdl = 2429/63109 | s2cid = 41565230 | hdl-access = free }} HLA-B*1502 occurs almost exclusively in people with ancestry across broad areas of Asia, but has a very low or absent frequency in European, Japanese, Korean and African populations.{{cite journal | vauthors = Leckband SG, Kelsoe JR, Dunnenberger HM, George AL, Tran E, Berger R, Müller DJ, Whirl-Carrillo M, Caudle KE, Pirmohamed M | title = Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing | journal = Clinical Pharmacology and Therapeutics | volume = 94 | issue = 3 | pages = 324–8 | date = September 2013 | pmid = 23695185 | pmc = 3748365 | doi = 10.1038/clpt.2013.103 }} However, the HLA-A*31:01 allele has been shown to be a strong predictor of both mild and severe adverse reactions, such as the DRESS form of severe cutaneous reactions, to carbamazepine among Japanese, Chinese, Korean, and Europeans.{{cite journal | vauthors = Garon SL, Pavlos RK, White KD, Brown NJ, Stone CA, Phillips EJ | title = Pharmacogenomics of off-target adverse drug reactions | journal = British Journal of Clinical Pharmacology | volume = 83 | issue = 9 | pages = 1896–1911 | date = September 2017 | pmid = 28345177 | pmc = 5555876 | doi = 10.1111/bcp.13294 }} It is suggested that carbamazepine acts as a potent antigen that binds to the antigen-presenting area of HLA-B*1502 alike, triggering an everlasting activation signal on immature CD8-T cells, thus resulting in widespread cytotoxic reactions like SJS/TEN.{{cite journal | vauthors = Jaruthamsophon K, Tipmanee V, Sangiemchoey A, Sukasem C, Limprasert P | title = HLA-B*15:21 and carbamazepine-induced Stevens-Johnson syndrome: pooled-data and in silico analysis | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 45553 | date = March 2017 | pmid = 28358139 | pmc = 5372085 | doi = 10.1038/srep45553 | bibcode = 2017NatSR...745553J }}

Carbamazepine has a potential for drug interactions.{{cite web|url=http://www.merck.com/mmpe/lexicomp/carbamazepine.html |title=Carbamazepine |date=February 2009 |author=Lexi-Comp |work=The Merck Manual Professional |archive-url=https://web.archive.org/web/20101103035532/http://www.merck.com/mmpe/lexicomp/carbamazepine.html |archive-date=3 November 2010 |url-status=live }} Retrieved on 3 May 2009. Drugs that decrease breaking down of carbamazepine or otherwise increase its levels include erythromycin,{{cite journal | vauthors = Stafstrom CE, Nohria V, Loganbill H, Nahouraii R, Boustany RM, DeLong GR | title = Erythromycin-induced carbamazepine toxicity: a continuing problem | journal = Archives of Pediatrics & Adolescent Medicine | volume = 149 | issue = 1 | pages = 99–101 | date = January 1995 | pmid = 7827672 | doi = 10.1001/archpedi.1995.02170130101025 | url = http://archpedi.ama-assn.org/cgi/pmidlookup?view=long&pmid=7827672 | url-status = live | archive-url = https://archive.today/20240525023120/https://www.webcitation.org/5uKvQB98w?url=http://archpedi.ama-assn.org/cgi/pmidlookup%3Fview=long&pmid=7827672 | archive-date = 25 May 2024 | url-access = subscription }} cimetidine, propoxyphene, and calcium channel blockers. Grapefruit juice raises the bioavailability of carbamazepine by inhibiting the enzyme CYP3A4 in the gut wall and in the liver. Lower levels of carbamazepine are seen when administered with phenobarbital, phenytoin, or primidone, which can result in breakthrough seizure activity.

Valproic acid and valnoctamide both inhibit microsomal epoxide hydrolase (mEH), the enzyme responsible for the breakdown of the active metabolite carbamazepine-10,11-epoxide into inactive metabolites.{{cite book | vauthors = Gonzalez FJ, Tukey RH | veditors = Brunton L, Lazo J, Parker K |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics |edition=11th |year=2006 |publisher=McGraw-Hill |location=New York |isbn=978-0-07-142280-2 |page=[https://archive.org/details/goodmangilmansph00brun_116/page/n104 79] |chapter=Drug Metabolism|title-link=Goodman & Gilman's The Pharmacological Basis of Therapeutics }} By inhibiting mEH, valproic acid and valnoctamide cause a build-up of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.

Carbamazepine, as an inducer of cytochrome P450 enzymes, may increase clearance of many drugs, decreasing their concentration in the blood to subtherapeutic levels and reducing their desired effects.{{cite web |url= http://www.emedicine.com/emerg/topic77.htm | work = eMedicine | title = Carbamazepine Toxicity |archive-url=https://web.archive.org/web/20080704144842/http://emedicine.com/emerg/topic77.htm |archive-date=4 July 2008 |url-status=live |date=2 February 2019 }} Drugs that are more rapidly metabolized with carbamazepine include warfarin, lamotrigine, phenytoin, theophylline, valproic acid, many benzodiazepines,{{cite book | vauthors = Moody D | veditors = Raymon LP, Mozayani A |title=Handbook of Drug Interactions: a Clinical and Forensic Guide |publisher=Humana |year=2004 |pages=[https://archive.org/details/handbookofdrugin0000unse/page/3 3–88] |chapter=Drug interactions with benzodiazepines |isbn=978-1-58829-211-7 |chapter-url-access=registration |chapter-url=https://archive.org/details/handbookofdrugin0000unse/page/3 }} and methadone.{{cite journal | vauthors = Schlatter J, Madras JL, Saulnier JL, Poujade F | title = [Drug interactions with methadone] | language = fr | journal = Presse Médicale | volume = 28 | issue = 25 | pages = 1381–4 | date = September 1999 | pmid = 10506872 | trans-title = Drug interactions with methadone }} Carbamazepine also increases the metabolism of the hormones in birth control pills and can reduce their effectiveness, potentially leading to unexpected pregnancies.

Carbamazepine is a sodium channel blocker.{{cite journal | vauthors = Rogawski MA, Löscher W, Rho JM | title = Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet | journal = Cold Spring Harbor Perspectives in Medicine | volume = 6 | issue = 5 | pages = a022780 | date = May 2016 | pmid = 26801895 | pmc = 4852797 | doi = 10.1101/cshperspect.a022780 }} It binds preferentially to voltage-gated sodium channels in their inactive conformation, which prevents repetitive and sustained firing of an action potential. Carbamazepine has effects on serotonin systems but the relevance to its antiseizure effects is uncertain. There is evidence that it is a serotonin releasing agent and possibly even a serotonin reuptake inhibitor.{{cite journal | vauthors = Dailey JW, Reith ME, Steidley KR, Milbrandt JC, Jobe PC | title = Carbamazepine-induced release of serotonin from rat hippocampus in vitro | journal = Epilepsia | volume = 39 | issue = 10 | pages = 1054–63 | date = October 1998 | pmid = 9776325 | doi = 10.1111/j.1528-1157.1998.tb01290.x | s2cid = 20382623 | doi-access = free }}{{cite journal | vauthors = Dailey JW, Reith ME, Yan QS, Li MY, Jobe PC | title = Carbamazepine increases extracellular serotonin concentration: lack of antagonism by tetrodotoxin or zero Ca2+ | journal = European Journal of Pharmacology | volume = 328 | issue = 2–3 | pages = 153–62 | date = June 1997 | pmid = 9218697 | doi = 10.1016/s0014-2999(97)83041-5 }}{{cite journal | vauthors = Kawata Y, Okada M, Murakami T, Kamata A, Zhu G, Kaneko S | title = Pharmacological discrimination between effects of carbamazepine on hippocampal basal, Ca(2+)- and K(+)-evoked serotonin release | journal = British Journal of Pharmacology | volume = 133 | issue = 4 | pages = 557–67 | date = June 2001 | pmid = 11399673 | pmc = 1572811 | doi = 10.1038/sj.bjp.0704104 }} It has been suggested that carbamazepine can also block voltage-gated calcium channels, which will reduce neurotransmitter release.{{cite journal | vauthors = Gambeta E, Chichorro JG, Zamponi GW | title = Trigeminal Neuralgia: an overview from pathophysiology to pharmacological treatments | journal = Molecular Pain |date = January 2020 | volume = 16 | pmid = 31908187| doi = 10.1177/1744806920901890 | pmc = 6985973 }}

File:Carbamazepine metabolism.svg, the active metabolite • bottom: carbamazepine-10,11-diol, an inactive metabolite, which is then glucuronidized]]

Carbamazepine is relatively slowly but practically completely absorbed after administration by mouth. Highest concentrations in the blood plasma are reached after 4 to 24 hours depending on the dosage form. Slow release tablets result in about 15% lower absorption and 25% lower peak plasma concentrations than ordinary tablets, as well as in less fluctuation of the concentration, but not in significantly lower minimum concentrations.{{cite web |title=Carbamazepine |url= https://pubchem.ncbi.nlm.nih.gov/compound/2554 |access-date=6 May 2021|work = PubChem | publisher = National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services }}{{cite book|title=Austria-Codex| veditors = Haberfeld H |at=Tegretol retard 400 mg-Filmtabletten|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2021|language=German}}

In the circulation, carbamazepine itself comprises 20 to 30% of total residues. The remainder is in the form of metabolites; 70 to 80% of residues is bound to plasma proteins. Concentrations in breast milk are 25 to 60% of those in the blood plasma.

Carbamazepine itself is not pharmacologically active. It is activated, mainly by CYP3A4, to carbamazepine-10,11-epoxide, which is solely responsible for the drug's anticonvulsant effects. The epoxide is then inactivated by microsomal epoxide hydrolase (mEH) to carbamazepine-trans-10,11-diol and further to its glucuronides. Other metabolites include various hydroxyl derivatives and carbamazepine-N-glucuronide.

The plasma half-life is about 35 to 40 hours when carbamazepine is given as single dose, but it is a strong inducer of liver enzymes, and the plasma half-life shortens to about 12 to 17 hours when it is given repeatedly. The half-life can be further shortened to 9–10 hours by other enzyme inducers such as phenytoin or phenobarbital. About 70% are excreted via the urine, almost exclusively in form of its metabolites, and 30% via the faeces.

Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG (now part of Novartis) in Basel, Switzerland, in 1953.{{cite book | vauthors = Scott DF | chapter = Chapter 8: Carbamazepine | title = The History of Epileptic Therapy: An Account of How Medication was Developed. | series = History of Medicine Series. | publisher = CRC Press | date = 1993 | isbn = 978-1-85070-391-4 }}{{cite journal |vauthors=Schindler W, Häfliger F |title=Über Derivate des Iminodibenzyls |journal=Helvetica Chimica Acta |year=1954 |volume=37 |issue=2 |pages=472–83 |doi=10.1002/hlca.19540370211}} It was first marketed as a drug to treat epilepsy in Switzerland in 1963 under the brand name Tegretol; its use for trigeminal neuralgia (formerly known as tic douloureux) was introduced at the same time. It has been used as an anticonvulsant and antiepileptic in the United Kingdom since 1965, and has been approved in the United States since 1968.

Carbamazepine was studied for bipolar disorder throughout the 1970s.{{cite journal | vauthors = Okuma T, Kishimoto A | title = A history of investigation on the mood stabilizing effect of carbamazepine in Japan | journal = Psychiatry and Clinical Neurosciences | volume = 52 | issue = 1 | pages = 3–12 | date = February 1998 | pmid = 9682927 | doi = 10.1111/j.1440-1819.1998.tb00966.x | s2cid = 8480811 }}

{{Main|Environmental impact of pharmaceuticals and personal care products}}

Carbamazepine and its bio-transformation products have been detected in wastewater treatment plant effluent{{cite journal | vauthors = Prosser RS, Sibley PK | title = Human health risk assessment of pharmaceuticals and personal care products in plant tissue due to biosolids and manure amendments, and wastewater irrigation | journal = Environment International | volume = 75 | pages = 223–33 | date = February 2015 | pmid = 25486094 | doi = 10.1016/j.envint.2014.11.020 | bibcode = 2015EnInt..75..223P }}{{rp|224}} and in streams receiving treated wastewater.{{cite journal | vauthors = Posselt M, Jaeger A, Schaper JL, Radke M, Benskin JP | title = Determination of polar organic micropollutants in surface and pore water by high-resolution sampling-direct injection-ultra high performance liquid chromatography-tandem mass spectrometry | journal = Environmental Science: Processes & Impacts | volume = 20 | issue = 12 | pages = 1716–1727 | date = December 2018 | pmid = 30350841 | doi = 10.1039/C8EM00390D | doi-access = free }} Field and laboratory studies have been conducted to understand the accumulation of carbamazepine in food plants grown in soil treated with sludge, which vary with respect to the concentrations of carbamazepine present in sludge and in the concentrations of sludge in the soil. Taking into account only studies that used concentrations commonly found in the environment, a 2014 review concluded that "the accumulation of carbamazepine into plants grown in soil amended with biosolids poses a de minimis risk to human health according to the approach."{{rp|227}}

Carbamazepine is available worldwide under many brand names including Tegretol.{{cite web |title=Carbamazepine |url=https://www.drugs.com/international/carbamazepine.html |website=Drugs.com |access-date=27 October 2019 |language=en}}

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• {{cite journal | vauthors = Iqbal MM, Gundlapalli SP, Ryan WG, Ryals T, Passman TE | title = Effects of antimanic mood-stabilizing drugs on fetuses, neonates, and nursing infants | journal = Southern Medical Journal | volume = 94 | issue = 3 | pages = 304–22 | date = March 2001 | pmid = 11284518 | doi = 10.1097/00007611-200194030-00007 | url = https://www.medscape.com/viewarticle/410736_4 | url-access = subscription }}
• {{cite book | title=Medical Genetics Summaries | chapter=Carbamazepine Therapy and HLA Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK321445/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=National Center for Biotechnology Information (NCBI) | year=2015 | pmid=28520367 | id=Bookshelf ID: NBK321445 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }}

{{refend}}

{{Commons category}}

• {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/carbamazepine | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Carbamazepine }}
• [https://www.nhs.uk/medicines/carbamazepine/ Carbamazepine]. UK National Health Service

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