Editing Phenytoin

{{Short description|Anti-seizure medication}}
{{Use dmy dates|date=June 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Verifiedfields     = changed
| Watchedfields      = changed
| verifiedrevid      = 457457901
| image              = Phenytoin structure.svg
| image_class        = skin-invert-image
| alt                = Structural formula of phenytoin
| width              = 150
| caption            =
| image2             = Phenytoin 3D ball.png
| alt2               = Ball-and-stick model of the phenytoin molecule
| width2             = 160

<!-- Clinical data -->
| pronounce          = {{IPAc-en|f|ə|ˈ|n|ɪ|t|oʊ|ᵻ|n|,_|ˈ|f|ɛ|n|ᵻ|t|ɔɪ|n}}
| tradename          = Dilantin, others<ref name=genericnames/>
| Drugs.com          = {{drugs.com|monograph|phenytoin}}
| MedlinePlus        = a682022
| DailyMedID         = Phenytoin
| pregnancy_AU       = D
| pregnancy_category = Toxic to reproduction
| routes_of_administration = [[Oral administration|By mouth]], [[intravenous]]
| class              = [[Anticonvulsant]]
| ATC_prefix         = N03
| ATC_suffix         = AB02
| ATC_supplemental   =

| legal_AU           = S4
| legal_BR           = C1
| legal_BR_comment   = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>
| legal_CA           = Rx-only
| legal_UK           = POM
| legal_US           = Rx-only
| legal_status       =

<!-- Pharmacokinetic data -->
| bioavailability    = 70–100% (oral), 24.4% (rectal)
| protein_bound      = 95%<ref name=AHFS2015>{{cite web|title=Phenytoin|url=https://www.drugs.com/monograph/phenytoin.html|publisher=The American Society of Health-System Pharmacists|access-date=22 August 2015|url-status=live|archive-url=https://web.archive.org/web/20150908063602/http://www.drugs.com/monograph/phenytoin.html|archive-date=8 September 2015}}</ref>
| metabolism         = [[Liver]]
| onset              = 10–30 min (intravenous)<ref name=Ros2010/>
| elimination_half-life = 10–22 hours<ref name=AHFS2015/>
| duration_of_action = 24 hours<ref name=Ros2010/>
| excretion          = Urinary (23–70%), bile<ref name="Parker Elliott Wright Nomof 1970 pp. 131–145">{{cite journal | vauthors = Parker KD, Elliott HW, Wright JA, Nomof N, Hine CH | title = Blood and urine concentrations of subjects receiving barbiturates, meprobamate, glutethimide, or diphenylhydantoin | journal = Clinical Toxicology | volume = 3 | issue = 1 | pages = 131–145 | date = March 1970 | pmid = 5520387 | doi = 10.3109/15563657008990108 | publisher = Informa UK Limited }}</ref>

<!-- Identifiers -->
| IUPHAR_ligand      = 2624
| CAS_number_Ref     = {{cascite|correct|??}}
| CAS_number         = 57-41-0
| ChEBI_Ref          = {{ebicite|changed|EBI}}
| ChEBI              = 8107
| PubChem            = 1775
| DrugBank_Ref       = {{drugbankcite|correct|drugbank}}
| DrugBank           = DB00252
| ChemSpiderID_Ref   = {{chemspidercite|correct|chemspider}}
| ChemSpiderID       = 1710
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = 6158TKW0C5
| KEGG_Ref           = {{keggcite|correct|kegg}}
| KEGG               = D00512
| ChEMBL_Ref         = {{ebicite|changed|EBI}}
| chemical_formula   = {{chem2|C15H12N2O2}}
| ChEMBL             = 16

<!-- Chemical data -->
| IUPAC_name         = 5,5-diphenylimidazolidine-2,4-dione
| C = 15 | H = 12 | N = 2 | O = 2
| smiles             = C1=CC=C(C=C1)C2(C(=O)NC(=O)N2)C3=CC=CC=C3
| StdInChI_Ref       = {{stdinchicite|changed|chemspider}}
| StdInChI           = 1S/C15H12N2O2/c18-13-15(17-14(19)16-13,11-7-3-1-4-8-11)12-9-5-2-6-10-12/h1-10H,(H2,16,17,18,19)
| StdInChIKey_Ref    = {{stdinchicite|changed|chemspider}}
| StdInChIKey        = CXOFVDLJLONNDW-UHFFFAOYSA-N
}}

<!-- Definition and medical uses -->
'''Phenytoin''' ('''PHT'''), sold under the brand name '''Dilantin''' among others,<ref name=genericnames/> is an [[anticonvulsant|anti-seizure medication]].<ref name=AHFS2015/> It is useful for the prevention of [[tonic-clonic seizure]]s (also known as grand mal seizures) and [[focal seizure]]s, but not [[absence seizure]]s.<ref name=AHFS2015/> The intravenous form, [[fosphenytoin]], is used for [[status epilepticus]] that does not improve with [[benzodiazepines]].<ref name=AHFS2015/>  It may also be used for certain [[heart arrhythmia]]s or [[neuropathic pain]].<ref name=AHFS2015/> It can be taken [[intravenously]] or by mouth.<ref name=AHFS2015/> The intravenous form generally begins working within 30 minutes and is effective for roughly 24 hours.<ref name=Ros2010>{{cite book| vauthors = Marx JA |title=Rosen's emergency medicine: concepts and clinical practice |date=2010 |publisher=Mosby/Elsevier |location=Philadelphia |isbn=9780323054720 |page=1352 |edition=7th |url= https://books.google.com/books?id=u7TNcpCeqx8C&pg=PA1352}}</ref> Blood levels can be measured to determine the proper dose.<ref name=AHFS2015/>

<!-- Side effects -->
Common side effects include nausea, stomach pain, loss of appetite, poor coordination, [[hypertrichosis|increased hair growth]], and [[Gingival hyperplasia|enlargement of the gums]].<ref name="AHFS2015" /> Potentially serious side effects include [[sleepiness]], [[self harm]], liver problems, [[bone marrow suppression]], [[hypotension|low blood pressure]], [[toxic epidermal necrolysis]],<ref name="AHFS2015" /> and atrophy of the [[cerebellum]].<ref>{{cite journal | vauthors = Algahtani H, Shirah B, Alqahtani AJ, Al-Malki AQ | title = Irreversible Cerebellar Atrophy as a Complication of Short-Term Phenytoin Exposure: Clinical Improvement Following Discontinuation of the Culprit | language = English | journal = Journal of Epilepsy Research | volume = 10 | issue = 2 | pages = 96–99 | date = December 2020 | pmid = 33659203 | pmc = 7903046 | doi = 10.14581/jer.20016 }}</ref><ref>{{cite journal | vauthors = Ferner R, Day R, Bradberry SM | title = Phenytoin and damage to the cerebellum - a systematic review of published cases | journal = Expert Opinion on Drug Safety | volume = 21 | issue = 7 | pages = 957–977 | date = July 2022 | pmid = 35325581 | doi = 10.1080/14740338.2022.2058487 }}</ref><ref>{{Citation | vauthors = Baba Y, Gaillard F |title=Phenytoin cerebellar degeneration |date=2017-04-10 |work=Radiopaedia.org |url=http://radiopaedia.org/articles/52506 |access-date=2024-12-22 |language=en |doi=10.53347/rid-52506 |doi-access=free }}</ref> There is evidence that use during pregnancy results in abnormalities in the baby.<ref name="AHFS2015" />  It appears to be safe to use when [[breastfeeding]].<ref name=AHFS2015/> [[Ethanol|Alcohol]] may interfere with the medication's effects.<ref name=AHFS2015/>

<!-- History, society, and culture -->
Phenytoin was first made in 1908 by the German chemist [[Heinrich Biltz]] and found useful for seizures in 1936.<ref>{{cite book| vauthors = Aicardi J |title=Epilepsy : a comprehensive textbook|date=2008|publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins |location=Philadelphia |isbn=9780781757775 |page=1431 |edition=2nd |url=https://books.google.com/books?id=3ZktoDp7tZoC&pg=PA1431}}</ref><ref>{{cite book| vauthors = Wolfson AB |title=Harwood-Nuss' clinical practice of emergency medicine|date=2010|publisher=Lippincott Williams & Wilkins |location=Philadelphia, PA |isbn=9780781789431 |page=1415 |edition=5th |url=https://books.google.com/books?id=Idb0Z658lFQC&pg=PT1448 |access-date=9 June 2016}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> Phenytoin is available as a [[generic medication]].<ref name=Ric2013>{{cite book| vauthors = Hamilton RJ |title=Tarascon pocket pharmacopoeia|date=2013|publisher=Jones & Bartlett Learning|location=Burlington, MA.|isbn=9781449673635|page=294|edition=14|url=https://books.google.com/books?id=Ti4xt1-9fLkC&pg=PA294}}</ref>  In 2020, it was the 260th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web | title = The Top 300 of 2020 | url = https://clincalc.com/DrugStats/Top300Drugs.aspx | website = ClinCalc | access-date = 7 October 2022}}</ref><ref>{{cite web | title = Phenytoin - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Phenytoin | access-date = 7 October 2022}}</ref>

==Medical uses==

===Seizures===
* [[Tonic-clonic seizures]]: Mainly used in the prophylactic management of tonic-clonic seizures with complex symptomatology (psychomotor seizures). A period of 5–10 days of dosing may be required to achieve anticonvulsant effects.{{cn|date=January 2025}}
* [[Focal seizures]]: Mainly used to protect against the development of focal seizures with complex symptomatology (psychomotor and [[temporal lobe seizure]]s). Also effective in controlling focal seizures with autonomic symptoms.{{cn|date=January 2025}}
* [[Absence seizures]]: Not used in treatment of pure absence seizures due to risk for increasing frequency of seizures. However, can be used in combination with other anticonvulsants during combined absence and tonic-clonic seizures.{{cn|date=January 2025}}
* Seizures during surgery: A 2018 meta-analysis found that early antiepileptic treatment with either phenytoin or phenobarbital reduced the risk of seizure in the first week after neurosurgery for brain tumors.<ref>{{cite journal | vauthors = Joiner EF, Youngerman BE, Hudson TS, Yang J, Welch MR, McKhann GM, Neugut AI, Bruce JN | title = Effectiveness of perioperative antiepileptic drug prophylaxis for early and late seizures following oncologic neurosurgery: a meta-analysis | journal = Journal of Neurosurgery | volume = 130 | issue = 4 | pages = 1274–1282 | date = April 2018 | pmid = 29701546 | doi = 10.3171/2017.10.JNS172236 | doi-access = free }}</ref>
* [[Status epilepticus]]: Considered after failed treatment using a [[benzodiazepine]] due to slow [[onset of action]].<ref name=Lexi2014>{{cite journal|title=Phenytoin|journal=Lexi-Comp Online|url=http://online.lexi.com/lco/action/doc/retrieve/docid/essential_ashp/410258#uses-nested|access-date=18 April 2014|url-status=live|archive-url=https://web.archive.org/web/20160304050234/http://online.lexi.com/lco/action/doc/retrieve/docid/essential_ashp/410258#uses-nested|archive-date=4 March 2016}}</ref>
Though phenytoin has been used to treat seizures in infants, as of 2023, its effectiveness in this age group has been evaluated in only one study. Due to the lack of a comparison group, the evidence is inconclusive.<ref>{{cite journal | vauthors =  Treadwell JR, Wu M, Tsou AY | title = Management of Infantile Epilepsies | date = 2022 | pmid = 36383706 | doi = 10.23970/ahrqepccer252 | journal = AHRQ Comparative Effectiveness Reviews | location = Rockville (MD) | publisher = Agency for Healthcare Research and Quality (US) | s2cid = 254357105 | id = Report No.: 22(23)-EHC004 2021-SR-01 }}</ref>

===Other===
* [[Arrhythmia|Abnormal heart rhythms]]: may be used in the treatment of [[ventricular tachycardia]] and sudden episodes of [[atrial tachycardia]] after other [[Antiarrhythmic agent|antiarrhythmic medications]] or [[cardioversion]] has failed.  It is a [[Antiarrhythmic agent#Class I agents|class Ib antiarrhythmic]].<ref>{{cite book| vauthors = McEvoy GK, Miller J, Snow EK |url= https://books.google.com/books?id=FaLXAAAACAAJ |title=AHFS Drug Information 2004|publisher=[[American Society of Health-System Pharmacists]] |year=2004 |pages=2117–2120| isbn=9781590742495 }}</ref>
* [[Digoxin toxicity]]: Intravenous phenytoin formulation is a medication of choice for arrhythmias caused by [[cardiac glycoside]] toxicity.
* [[Trigeminal neuralgia]]: Second choice drug to [[carbamazepine]].<ref>{{cite book | vauthors = Satoskar RS, Rege NB, Bhandarkar SD |title=Pharmacology and Pharmacotherapeutics | edition = 22nd | date = 2011 |publisher=Popular Prakashan Ltd. |isbn=9788179916582 |pages=219 }}</ref>

===Special considerations===
* Phenytoin has a narrow [[therapeutic index]]. Its therapeutic range for both anticonvulsant and antiarrhythmic effect is 10–20&nbsp;μg/mL.
* Avoid giving intramuscular formulation unless necessary due to skin cell death and local tissue destruction.
* Elderly patients may show earlier signs of toxicity.
* In the obese, ideal body weight should be used for dosing calculations.
* Pregnancy: [[Pregnancy category|Pregnancy category D]] due to risk of [[fetal hydantoin syndrome]] and fetal bleeding. However, optimal seizure control is very important during pregnancy so drug may be continued if benefits outweigh the risks. Due to decreased drug concentrations as a result of [[Maternal physiological changes in pregnancy|plasma volume expansion during pregnancy]], dose of phenytoin may need to be increased if only option for seizure control.
* Breastfeeding: The manufacturer does not recommend breastfeeding since low concentrations of phenytoin are excreted in breast milk.<ref name=PI>Phenytoin [package insert]. New York, NY: Pfizer Inc.; 2013. Accessed 2 November 2014.</ref>
* Liver disease: Do not use oral loading dose. Consider using decreased maintenance dose.
* Kidney disease: Do not use oral loading dose. Can begin with standard maintenance dose and adjust as needed.
* Intravenous use is contraindicated in patients with [[sinus bradycardia]], [[SA block|sinoatrial block]], second- or third-degree [[AV block|atrioventricular block]], [[Stokes-Adams syndrome]], or hypersensitivity to phenytoin, other [[hydantoin]]s or any ingredient in the respective formulation.

==Side effects==
{{more medical citations needed|section|date=June 2019}}
Common side effects include nausea, stomach pain, loss of appetite, poor coordination, [[hypertrichosis|increased hair growth]], and [[Gingival enlargement|enlargement of the gums]].<!-- <ref name=AHFS2015/> --> Potentially serious side effects include [[sleepiness]], [[self harm]], liver problems, [[bone marrow suppression]], [[hypotension|low blood pressure]], and [[toxic epidermal necrolysis]].<!-- <ref name=AHFS2015/> --> There is evidence that use during pregnancy results in abnormalities in the baby.<!-- <ref name=AHFS2015/> --> Its use appears to be safe during [[breastfeeding]].<!-- <ref name=AHFS2015/> --> [[Ethanol|Alcohol]] may interfere with the medication's effects.<ref name=AHFS2015/>

===Heart and blood vessels===
Severe [[hypotension|low blood pressure]] and abnormal heart rhythms can be seen with rapid infusion of IV phenytoin. IV infusion should not exceed 50&nbsp;mg/min in adults or 1–3&nbsp;mg/kg/min (or 50&nbsp;mg/min, whichever is slower) in children. Heart monitoring should occur during and after IV infusion. Due to these risks, oral phenytoin should be used if possible.<ref name="FDA drug label"/>

===Neurological===
At therapeutic doses, phenytoin may produce [[nystagmus]] on lateral gaze. At toxic doses, patients experience vertical nystagmus, [[diplopia|double vision]], [[sedation]], slurred speech, cerebellar [[ataxia]], and [[tremor]].<ref>{{cite web |title=Dilantin Toxicity |url= http://www.fpnotebook.com/neuro/pharm/DlntnTxcty.htm |url-status=live |archive-url= https://web.archive.org/web/20140419011512/http://www.fpnotebook.com/neuro/pharm/DlntnTxcty.htm |archive-date=19 April 2014 | publisher = Family Practice Notebook, LLC }}</ref> If phenytoin is stopped abruptly, this may result in increased seizure frequency, including [[status epilepticus]].<ref name="FDA drug label"/><ref name=PI />

Phenytoin may accumulate in the [[cerebral cortex]] over long periods of time which can cause [[atrophy]] of the [[cerebellum]]. The degree of atrophy is related to the duration of phenytoin treatment and is not related to dosage of the medication.<ref>{{cite journal | vauthors = De Marcos FA, Ghizoni E, Kobayashi E, Li LM, Cendes F | title = Cerebellar volume and long-term use of phenytoin | journal = Seizure | volume = 12 | issue = 5 | pages = 312–315 | date = July 2003 | pmid = 12810345 | doi = 10.1016/s1059-1311(02)00267-4 | doi-access = free }}</ref>

Phenytoin is known to be a causal factor in the development of [[peripheral neuropathy]].<ref>{{cite book | vauthors = Donofrio PD | chapter = Medicine Related Neuropathy | veditors = Donofrio PD |title=Textbook of Peripheral Neuropathy |date=2012 |publisher=Demos Medical Publishing |location=New York |isbn=978-1-936287-10-9 | page = 208 | chapter-url = https://books.google.com/books?id=ozIep65VKkYC&pg=PA208 }}</ref>

===Blood===
Folate is present in food in a polyglutamate form, which is then converted into monoglutamates by [[Gamma-glutamyl hydrolase|intestinal conjugase]] to be absorbed by the jejunum. Phenytoin acts by inhibiting this enzyme, thereby causing [[folate deficiency]], and thus [[megaloblastic anemia]].<ref>{{cite journal | vauthors = Carl GF, Smith ML | title = Phenytoin-folate interactions: differing effects of the sodium salt and the free acid of phenytoin | journal = Epilepsia | volume = 33 | issue = 2 | pages = 372–375 | year = 1992 | pmid = 1547769 | doi = 10.1111/j.1528-1157.1992.tb02330.x | s2cid = 40927589 }}</ref>
Other side effects may include: [[agranulocytosis]],<ref>{{cite journal | vauthors = Sharafuddin MJ, Spanheimer RG, McClune GL | title = Phenytoin-induced agranulocytosis: a nonimmunologic idiosyncratic reaction? | journal = Acta Haematologica | volume = 86 | issue = 4 | pages = 212–213 | year = 1991 | pmid = 1805490 | doi = 10.1159/000204838 }}</ref> [[aplastic anemia]],<ref>{{cite journal | vauthors = Handoko KB, Souverein PC, van Staa TP, Meyboom RH, Leufkens HG, Egberts TC, van den Bemt PM | title = Risk of aplastic anemia in patients using antiepileptic drugs | journal = Epilepsia | volume = 47 | issue = 7 | pages = 1232–1236 | date = July 2006 | pmid = 16886988 | doi = 10.1111/j.1528-1167.2006.00596.x | hdl-access = free | s2cid = 25327883 | hdl = 1874/27341 }}</ref> [[leukopenia|decreased white blood cell count]],<ref>{{cite book | vauthors = Workman ML, Lacharity LA |title=Understanding Pharmacology: Essentials for Medication Safety |date=2016 |location=St. Louis, Missouri | publisher = Elsevier Health Sciences |isbn=978-1-4557-3976-9 |edition=2nd | url = https://books.google.com/books?id=AiHmCgAAQBAJ&pg=PA302 }}</ref> and [[thrombocytopenia|a low platelet count]].<ref>{{cite web | vauthors = Hamblin TJ |title=Aplastic anaemia |date=August 2005 | work = NetDoctor |url= http://www.netdoctor.co.uk/diseases/facts/aplasticanaemia.htm |access-date=8 July 2013 |url-status=live |archive-url=https://web.archive.org/web/20130212114642/http://www.netdoctor.co.uk/diseases/facts/aplasticanaemia.htm |archive-date=12 February 2013 }}</ref>

===Pregnancy===
Phenytoin is a known [[teratogenesis|teratogen]], since children exposed to phenytoin are at a higher risk of [[birth defects]] than children born to women without epilepsy and to women with untreated epilepsy.<ref name="Bromley_2014">{{cite journal | vauthors = Bromley R, Weston J, Adab N, Greenhalgh J, Sanniti A, McKay AJ, Tudur Smith C, Marson AG | title = Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child | journal = The Cochrane Database of Systematic Reviews | volume = 2014 | issue = 10 | pages = CD010236 | date = October 2014 | pmid = 25354543 | pmc = 7390020 | doi = 10.1002/14651858.CD010236.pub2 | collaboration = Cochrane Epilepsy Group }}</ref><ref name="Bromley_2023">{{cite journal | vauthors = Bromley R, Adab N, Bluett-Duncan M, Clayton-Smith J, Christensen J, Edwards K, Greenhalgh J, Hill RA, Jackson CF, Khanom S, McGinty RN, Tudur Smith C, Pulman J, Marson AG | title = Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 8 | pages = CD010224 | date = August 2023 | pmid = 37647086 | pmc = 10463554 | doi = 10.1002/14651858.CD010224.pub3 }}</ref> The birth defects, which occur in approximately 6% of exposed children, include [[neural tube defect]]s, [[Congenital heart defect|heart defects]] and [[Craniofacial abnormality|craniofacial abnormalities]], including broad nasal bridge, cleft lip and palate, and [[Microcephaly|smaller than normal head]].<ref name="Bromley_2023" /><ref>{{cite book |title=Obstetrics and Gynecology |vauthors=Beckmann CR |publisher=Lippincott Williams & Wilkins |year=2002 |edition=4th |location=Baltimore |display-authors=etal}}</ref> The effect on IQ cannot be determined as no study involves phenytoin as monotherapy, however poorer language abilities and [[delayed motor development]] may have been associated with maternal use of phenytoin during pregnancy.<ref name="Bromley_2014" /> This syndrome resembles the well-described [[Fetal Alcohol Syndrome|fetal alcohol syndrome]].<ref>{{cite web | vauthors = ((National Task Force on Fetal Alcohol Syndrome and Fetal Alcohol Effect)) | title = Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis | date = July 2004 | url = https://www.cdc.gov/ncbddd/fasd/documents/fas_guidelines_accessible.pdf | work = National Center on Birth Defects and Developmental Disabilities | publisher = Centers for Disease Control and Prevention; U.S. Department of Health and Human Services }}</ref> and has been referred to as "[[fetal hydantoin syndrome]]". Some recommend avoiding polytherapy and maintaining the minimal dose possible during pregnancy, but acknowledge that current data fails to demonstrate a dose effect on the risk of birth defects.<ref name="Bromley_2014" /><ref name="Bromley_2023" /> Data now being collected by the Epilepsy and Antiepileptic Drug Pregnancy Registry may one day answer this question definitively.

===Cancer===
There is no good evidence to suggest that phenytoin is a human [[carcinogen]].<ref>Report on Carcinogens, Eleventh Edition (PB2005-104914, 2004) p III-216.</ref><ref name="pmid3373561">{{cite journal | vauthors = Maeda T, Sano N, Togei K, Shibata M, Izumi K, Otsuka H | title = Lack of carcinogenicity of phenytoin in (C57BL/6 x C3H)F1 mice | journal = Journal of Toxicology and Environmental Health | volume = 24 | issue = 1 | pages = 111–119 | year = 1988 | pmid = 3373561 | doi = 10.1080/15287398809531144 }}</ref> However, lymph node abnormalities have been observed, including malignancies.<ref>{{cite journal | vauthors = Schwinghammer TL, Howrie DL | title = Phenytoin-induced lymphadenopathy | journal = Drug Intelligence & Clinical Pharmacy | volume = 17 | issue = 6 | pages = 460–462 | date = June 1983 | pmid = 6861635 | doi = 10.1177/106002808301700608 | s2cid = 37504937 }}</ref>

===Mouth===
Phenytoin has been associated with drug-induced [[gingival enlargement]] (overgrowth of the gums), probably due to above-mentioned folate deficiency; indeed, evidence from a [[randomized controlled trial]] suggests that folic acid supplementation can prevent gingival enlargement in children who take phenytoin.<ref>{{cite journal | vauthors = Arya R, Gulati S, Kabra M, Sahu JK, Kalra V | title = Folic acid supplementation prevents phenytoin-induced gingival overgrowth in children | journal = Neurology | volume = 76 | issue = 15 | pages = 1338–1343 | date = April 2011 | pmid = 21482950 | pmc = 3090066 | doi = 10.1212/WNL.0b013e3182152844 }}
</ref> Plasma concentrations needed to induce gingival lesions have not been clearly defined.  Effects consist of the following: bleeding upon probing, increased gingival [[exudate]], pronounced gingival inflammatory response to plaque levels, associated in some instances with bone loss but without tooth detachment.

===Skin===
[[Hypertrichosis]], [[Stevens–Johnson syndrome]], [[purple glove syndrome]], rash, [[exfoliative dermatitis]], [[pruritis|itching]], [[hirsutism|excessive hairiness]], and coarsening of facial features can be seen in those taking phenytoin.

Phenytoin therapy has been linked to the life-threatening skin reactions [[Stevens–Johnson syndrome]] (SJS) and [[toxic epidermal necrolysis]] (TEN). These conditions are significantly more common in patients with a particular [[HLA-B]] [[allele]], [[HLA-B75|HLA-B*1502]].<ref name="pmid17509004">{{cite journal | vauthors = Man CB, Kwan P, Baum L, Yu E, Lau KM, Cheng AS, Ng MH | title = Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese | journal = Epilepsia | volume = 48 | issue = 5 | pages = 1015–1018 | date = May 2007 | pmid = 17509004 | doi = 10.1111/j.1528-1167.2007.01022.x | s2cid = 34728720 | doi-access = free }}</ref> This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians.

Phenytoin is primarily metabolized to its inactive form by the enzyme [[CYP2C9]]. Variations within the CYP2C9 gene that result in decreased enzymatic activity have been associated with increased phenytoin concentrations, as well as reports of drug toxicities due to these increased concentrations.<ref>{{cite journal | vauthors = Caudle KE, Rettie AE, Whirl-Carrillo M, Smith LH, Mintzer S, Lee MT, Klein TE, Callaghan JT | title = Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing | journal = Clinical Pharmacology and Therapeutics | volume = 96 | issue = 5 | pages = 542–548 | date = November 2014 | pmid = 25099164 | pmc = 4206662 | doi = 10.1038/clpt.2014.159 }}</ref> The [[U.S. Food and Drug Administration]] (FDA) notes on the phenytoin drug label that since strong evidence exists linking HLA-B*1502 with the risk of developing SJS or TEN in patients taking [[carbamazepine]], consideration should be given to avoiding phenytoin as an alternative to carbamazepine in patients carrying this allele.<ref>{{cite web|title=DILANTIN- phenytoin sodium capsule, extended release|url=http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8848de76-8d74-4620-bcc7-a86a596e5dd9|access-date=12 March 2015|url-status=live|archive-url=https://web.archive.org/web/20150402175051/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8848de76-8d74-4620-bcc7-a86a596e5dd9|archive-date=2 April 2015}}</ref>

===Immune system===
Phenytoin has been known to cause drug-induced [[Systemic lupus erythematosus|lupus]].<ref name="pmid12952753">{{cite journal | vauthors = Scheinfeld N | title = Phenytoin in cutaneous medicine: its uses, mechanisms and side effects | journal = Dermatology Online Journal | volume = 9 | issue = 3 | pages = 6 | date = August 2003 | pmid = 12952753 | doi = 10.5070/D32197W4T4 | url = http://dermatology.cdlib.org/93/reviews/dilantin/scheinfeld.html | url-status = live | archive-url = https://web.archive.org/web/20080829155639/http://dermatology.cdlib.org/93/reviews/dilantin/scheinfeld.html | archive-date = 29 August 2008 }}</ref>

Phenytoin is also associated with induction of reversible [[IgA deficiency]].<ref name="pmid6181216">{{cite journal | vauthors = Gilhus NE, Aarli JA | title = The reversibility of phenytoin-induced IgA deficiency | journal = Journal of Neurology | volume = 226 | issue = 1 | pages = 53–61 | year = 1981 | pmid = 6181216 | doi = 10.1007/BF00313318 | s2cid = 23984720 }}</ref>

===Psychological===
Phenytoin may increase risk of suicidal thoughts or behavior. People on phenytoin should be monitored for any changes in mood, the development or worsening depression, and/or any thoughts or behavior of suicide.<ref name=PI />

===Bones===
Chronic phenytoin use has been associated with decreased bone density and increased bone fractures. Phenytoin induces metabolizing enzymes in the liver. This leads to increased metabolism of [[vitamin D]], thus decreased vitamin D levels. [[Vitamin D deficiency]], as well as [[Hypocalcemia|low calcium]] and [[Hypophosphatemia|phosphate]] in the blood cause decreased bone mineral density.<ref name=PI />

== Interactions ==

Phenytoin is an inducer of the [[CYP3A4]] and [[CYP2C9]] families of the [[P450]] enzyme responsible for the liver's degradation of various drugs.<ref>{{cite journal | vauthors = Cuttle L, Munns AJ, Hogg NA, Scott JR, Hooper WD, Dickinson RG, Gillam EM | title = Phenytoin metabolism by human cytochrome P450: involvement of P450 3A and 2C forms in secondary metabolism and drug-protein adduct formation | journal = Drug Metabolism and Disposition | volume = 28 | issue = 8 | pages = 945–950 | date = August 2000 | pmid = 10901705 }}</ref>

A 1981 study by the [[National Institutes of Health]] showed that [[antacids]] administered concomitantly with phenytoin "altered not only the extent of absorption but also appeared to alter the rate of absorption.  Antacids administered in a peptic ulcer regimen may decrease the AUC of a single dose of phenytoin. Patients should be cautioned against concomitant use of antacids and phenytoin."<ref>{{cite journal | vauthors = Carter BL, Garnett WR, Pellock JM, Stratton MA, Howell JR | title = Effect of antacids on phenytoin bioavailability | journal = Therapeutic Drug Monitoring | volume = 3 | issue = 4 | pages = 333–340 | date = 1981 | pmid = 7336470 | doi = 10.1097/00007691-198104000-00003 | s2cid = 26099092 }}</ref>

[[Warfarin]] and [[trimethoprim]] increase serum phenytoin levels and prolong the serum half-life of phenytoin by inhibiting its metabolism. Consider using other options if possible.<ref>{{cite web|title=Lexi-Comp Online Interaction Lookup|url=http://www.lexi.com/institutions/online.jsp?id=databases|publisher=Lexi-Comp|url-status=live|archive-url=https://web.archive.org/web/20140419030045/http://www.lexi.com/institutions/online.jsp?id=databases|archive-date=19 April 2014}}</ref>

In general, phenytoin can interact with the following drugs:{{cn|date=January 2025}}
* Antidepressant drugs
* Antifungal drugs such as [[fluconazole]], [[ketoconazole]]
* antibiotics such as [[metronidazole]], [[chloramphenicol]], [[clarithromycin]], [[azithromycin]]
* Cortones (such as [[betamethasone]], dexamethasone, [[hydrocortisone]] and [[prednisolone]]
* [[L-DOPA]] (phenytoin can cause the beneficial effect of levodopa to disappear.)

==Pharmacology==
===Mechanism of action===
[[File:Phenytoin sodium mechanism of action.png|thumb|The mechanism of action of phenytoin sodium. Sodium channels are: 1) Closed 2) Open 3) Inactive (phenytoin effect)]]
Phenytoin is believed to protect against seizures by causing voltage-dependent block of [[voltage gated sodium channel]]s.<ref>{{cite journal | vauthors = Rogawski MA, Löscher W | title = The neurobiology of antiepileptic drugs | journal = Nature Reviews. Neuroscience | volume = 5 | issue = 7 | pages = 553–564 | date = July 2004 | pmid = 15208697 | doi = 10.1038/nrn1430 | s2cid = 2201038 | url = https://zenodo.org/record/1233562 }}</ref> This blocks sustained high frequency repetitive firing of [[action potentials]]. This is accomplished by reducing the amplitude of sodium-dependent action potentials through enhancing steady-state inactivation. Sodium channels exist in three main conformations: the resting state, the open state, and the inactive state.

Phenytoin binds preferentially to the inactive form of the sodium channel. Because it takes time for the bound drug to dissassociate from the inactive channel, there is a time-dependent block of the channel. Since the fraction of inactive channels is increased by membrane [[depolarization]] as well as by repetitive firing, the binding to the inactive state by phenytoin sodium can produce voltage-dependent, use-dependent and time-dependent block of sodium-dependent action potentials.<ref>lippincots modern pharmacology with clinical applications pg no:377 5th Edition</ref>

The primary site of action appears to be the [[motor cortex]] where spread of seizure activity is inhibited.<ref>{{cite web | title = Dilantin | date =  2015 | work =  MIMS | url = https://www.mims.com/Hongkong/drug/info/Dilantin/?type=full#Actions | archive-url= https://web.archive.org/web/20140810173319/http://mims.com/Hongkong/drug/info/Dilantin/?type=full | archive-date=10 August 2014 }}</ref> Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of [[post-tetanic potentiation]] at synapses which prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures.<ref name="FDA drug label">{{cite web|title=Parenteral Dilantin (Phenytoin Sodium Injection, USP) | date = October 2011 | work = Parke-Davis | publisher = U.S. Food and Drug Administration |url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/010151s036lbl.pdf |access-date=18 April 2014|url-status=live|archive-url= https://web.archive.org/web/20140419011525/http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/010151s036lbl.pdf |archive-date=19 April 2014}}</ref>

===Pharmacokinetics===
Phenytoin elimination kinetics show mixed-order, non-linear elimination behaviour at therapeutic concentrations. Where phenytoin is at low concentration it is cleared by [[first order kinetics]], and at high concentrations by [[zero order kinetics]]. A small increase in dose may lead to a large increase in drug concentration as elimination becomes saturated. The time to reach steady state is often longer than 2 weeks.<ref>{{Cite book|url = http://ebooks.cambridge.org/chapter.jsf?bid=CBO9781139103992&cid=CBO9781139103992A081|doi = 10.1017/CBO9781139103992|title = Introduction to Epilepsy|year = 2012|publisher = Cambridge University Press|isbn = 9781139103992| veditors = Alarcon G, Antonio V |access-date = 17 January 2013|archive-date = 25 September 2020|archive-url = https://web.archive.org/web/20200925004650/https://www.cambridge.org/core/books/introduction-to-epilepsy/69E0223B157629447A55460FFD7B2EE6|url-status = dead}}</ref><ref>{{cite book | chapter = Chapter 67 Antiepileptic drug pharmacokinetics and therapeutic drug monitoring | pages =358–366 | vauthors = Patsalos PN | date = 2012 | title = Antiepileptic drug pharmacokinetics and therapeutic drug monitoring | publisher = Cambridge University Press }}</ref><ref>{{cite web |url=http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9993 |title=PNYFR - Clinical: Phenytoin, Total and Free, Serum |access-date=17 January 2013 |url-status=dead |archive-url=https://web.archive.org/web/20130301003954/http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9993 |archive-date=1 March 2013 }}</ref><ref>{{cite journal | vauthors = Donahue S, Flockhart DA, Abernethy DR | title = Ticlopidine inhibits phenytoin clearance | journal = Clinical Pharmacology and Therapeutics | volume = 66 | issue = 6 | pages = 563–568 | date = December 1999 | pmid = 10613611 | doi = 10.1053/cp.1999.v66.103277001 | s2cid = 25980868 }}</ref>

==History==
Phenytoin (diphenylhydantoin) was first synthesized by German chemist [[Heinrich Biltz]] in 1908.<ref name=Biltz>{{ cite journal | vauthors = Biltz H | journal = Chemische Berichte |trans-title=Constitution of the Products of the Interaction of Substituted Carbamides on Benzil and Certain New Methods for the Preparation of 5,5-Diphenylhydantoin | title = Über die Konstitution der Einwirkungsprodukte von substituierten Harnstoffen auf Benzil und über einige neue Methoden zur Darstellung der 5,5-Diphenyl-hydantoine | language = de | year = 1908 | volume  = 41 | issue = 1 | pages = 1379–1393 | doi = 10.1002/cber.190804101255 | url = https://zenodo.org/record/1426279 }}</ref>
Biltz sold his discovery to Parke-Davis, which did not find an immediate use for it. In 1938, other physicians, including [[H. Houston Merritt]] and [[Tracy Putnam]], discovered phenytoin's usefulness for controlling seizures, without the sedative effects associated with [[phenobarbital]].<ref>{{cite journal | vauthors = Friedlander WJ | title = Putnam, Merritt, and the discovery of Dilantin | journal = Epilepsia | volume = 27 | issue = Suppl 3 | pages = S1-20 | date = 1986 | pmid = 3527690 | doi = 10.1111/j.1528-1157.1986.tb05743.x | s2cid = 7761284 }}</ref>

According to ''Goodman and Gilman's Pharmacological Basis of Therapeutics'':

<blockquote>In contrast to the earlier accidental discovery of the antiseizure properties of [[potassium bromide]] and phenobarbital, phenytoin was the product of a search among nonsedative structural relatives of phenobarbital for agents capable of suppressing electroshock convulsions in laboratory animals.<ref>{{ cite book | title = Goodman and Gilman's Pharmacological Basis of Therapeutics | edition = 10th | location = New York | publisher = McGraw-Hill | year = 2001 }}</ref></blockquote>

It was approved by the FDA in 1953 for use in seizures.{{cn|date=January 2025}}

[[Jack Dreyfus]], founder of the [[Dreyfus Fund]], became a major proponent of phenytoin as a means to control nervousness and [[clinical depression|depression]] when he received a prescription for Dilantin in 1966. He has claimed to have supplied large amounts of the drug to [[Richard Nixon]] throughout the late 1960s and early 1970s, although this is disputed by former White House aides<ref>{{cite news | vauthors = Stout D |date=31 August 2000 |title=2 Nixon Aides Skeptical About Report That He Took Drug |url=https://www.nytimes.com/2000/08/31/us/2-nixon-aides-skeptical-about-report-that-he-took-drug.html |work=[[The New York Times]] |access-date=6 February 2020}}</ref> and Presidential historians.<ref>{{cite web |title=New Nixon Biography Gives Salacious Details | vauthors = Campbell J |date=6 January 2006 |access-date=7 August 2021 |url=https://abcnews.go.com/Politics/story?id=123021 |website=[[ABC News (United States)|ABC News]] |publication-place=[[New York City]], [[New York (state)|New York]], United States of America | veditors = Muir D |editor1-link=David Muir |publisher=[[American Broadcasting Company]] ([[Walt Disney Television]]) }}</ref>
Dreyfus' experience with phenytoin is outlined in his book, ''A Remarkable Medicine Has Been Overlooked''.<ref>{{cite book | author = Dreyfus J | title = A Remarkable Medicine Has Been Overlooked: Including an Autobiography and the Clinical Section of the Broad Range of Use of Phenytoin | publisher = Continuum International Publishing Group | year = 1998 | isbn = 978-0-8264-1069-6 | url-access = registration | url = https://archive.org/details/remarkablemedic000drey }}</ref> Despite more than $70&nbsp;million in personal financing, his push to see phenytoin evaluated for alternative uses has had little lasting effect on the medical community.  This was partially because [[Parke-Davis]] was reluctant to invest in a drug nearing the end of its patent life, and partially due to mixed results from various studies.{{cn|date=January 2025}}

In 2008, the drug was put on the FDA's Potential Signals of Serious Risks List to be further evaluated for approval. The list identifies medications with which the FDA has identified potential safety issues, but has not yet identified a causal relationship between the drug and the listed risk. To address this concern, the Warnings and Precautions section of the labeling for Dilantin injection was updated to include additional information about [[Purple glove syndrome]] in November 2011.<ref>{{cite web|title=AERS data|url=https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm085914.htm|publisher=FDA|access-date=18 April 2014|url-status=live|archive-url=https://web.archive.org/web/20140419025736/https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm085914.htm|archive-date=19 April 2014}}</ref>

==Society and culture==

===Economics===
Phenytoin is available as a generic medication.<ref name=Ric2013/>

Since September 2012, the marketing licence in the UK has been held by Flynn Pharma Ltd, of Dublin, [[Ireland]], and the product, although identical, has been called Phenytoin Sodium ''xx''mg Flynn Hard Capsules. (The ''xx''mg in the name refers to the strength—for example "Phenytoin sodium 25&nbsp;mg Flynn Hard Capsules").<ref>{{cite web | title = Phenytoin Sodium Flynn Hard Capsules...Marketing authorisation holder | work = Flynn Pharma patient information leaflet at the electronic Medicines Compendium | date = 24 April 2014 | url = https://www.medicines.org.uk/emc/medicine/28811/SPC/Phenytoin+Sodium+Flynn+Hard+Capsules+25mg%2C+50mg%2C+100mg+and+300mg/ | archive-url = https://web.archive.org/web/20170115195136/https://www.medicines.org.uk/emc/medicine/28811/SPC/Phenytoin+Sodium+Flynn+Hard+Capsules+25mg%2C+50mg%2C+100mg+and+300mg/ | archive-date=15 January 2017 | access-date = 13 May 2014 }}</ref>  The capsules are still made by [[Pfizer]]'s Goedecke subsidiary's plant in [[Freiburg]], Germany, and they still have Epanutin printed on them.<ref>{{cite web | url = https://www.mediguard.org/alerts/alert/2235.html | title = Healthcare Professionals Advised That Epanutin Capsules Are Only To Be Available Under The Generic Name | publisher = MediGuard | location = Durham, NC | date = 2 October 2012 | archive-url = https://web.archive.org/web/20140514054718/https://www.mediguard.org/alerts/alert/2235.html | archive-date=14 May 2014 | access-date= 13 May 2014 }}</ref> After Pfizer's sale of the UK marketing licence to Flynn Pharma, the price of a 28-pack of 25&nbsp;mg phenytoin sodium capsules marked Epanutin rose from 66p (about $0.88) to {{GBP|15.74}} (about $25.06). Capsules of other strengths also went up in price by the same factor—2,384%,<ref>{{cite web | url = http://www.telegraph.co.uk/health/healthnews/9604683/Pharma-firm-hikes-cost-of-epilepsy-drug-24-times.html | title = Pharma firm hikes cost of epilepsy drug 24 times | vauthors = Adams S | work = Daily Telegraph | location =  London | date = 12 October 2012 | archive-url = https://web.archive.org/web/20121013041043/http://www.telegraph.co.uk/health/healthnews/9604683/Pharma-firm-hikes-cost-of-epilepsy-drug-24-times.html | access-date = 13 May 2014 | archive-date = 13 October 2012 }}</ref> costing the UK's [[National Health Service]] an extra {{GBP|43 million}} (about $68.44&nbsp;million) a year.<ref>{{cite web | url = http://www.pulsetoday.co.uk/commissioning/commissioning-topics/prescribing/price-of-anti-epilepsy-drug-rockets/20000936.article#.U3Jez6G-ZQI | title = Price of anti-epilepsy drug rockets | vauthors = Gould M | work = Pulse | location = London | date = 21 November 2012 | archive-url = https://web.archive.org/web/20121128130259/http://www.pulsetoday.co.uk/commissioning/commissioning-topics/prescribing/price-of-anti-epilepsy-drug-rockets/20000936.article | archive-date=28 November 2012 | access-date = 13 May 2014 }}</ref>  The companies were referred to the [[Competition and Markets Authority]] (CMA) who found that they had exploited their dominant position in the market to charge "excessive and unfair" prices.<ref>{{cite news| vauthors = White M |title=Pharma market abuse isn't picked up fast enough|url=http://www.hsj.co.uk/comment/pharma-market-abuse-isnt-picked-up-fast-enough/5089545.article |access-date=6 October 2015 |work=Health Service Journal |date=12 August 2015|url-status=live|archive-url=https://web.archive.org/web/20151007030951/http://www.hsj.co.uk/comment/pharma-market-abuse-isnt-picked-up-fast-enough/5089545.article#.VhPzkUpfZ1A|archive-date=7 October 2015}}</ref>

The CMA imposed a record {{GBP|84.2 million}} fine on the manufacturer Pfizer, and a {{GBP|5.2 million}} fine on the distributor Flynn Pharma and ordered the companies to reduce their prices.<ref>{{Cite press release |url=https://www.gov.uk/government/news/cma-fines-pfizer-and-flynn-90-million-for-drug-price-hike-to-nhs|title=CMA fines Pfizer and Flynn £90 million for drug price hike to NHS |publisher=www.gov.uk |access-date=7 December 2016|url-status=live |archive-url=https://web.archive.org/web/20161207081839/https://www.gov.uk/government/news/cma-fines-pfizer-and-flynn-90-million-for-drug-price-hike-to-nhs |archive-date=7 December 2016}}</ref>

===Brand names===
Phenytoin is marketed under many brand names worldwide.<ref name=genericnames>{{cite web | work = Drugs.com | url = https://www.drugs.com/international/phenytoin.html | title = International trade names for phenytoin | archive-url = https://web.archive.org/web/20160223001607/http://www.drugs.com/international/phenytoin.html | archive-date= 23 February 2016| access-date = 27 February 2016 }}</ref>

In the US, Dilantin is marketed by [[Viatris]] after Upjohn was spun off from Pfizer.<ref>{{cite web | title=Pfizer Completes Transaction to Combine Its Upjohn Business with Mylan | publisher=Pfizer | via=Business Wire | date=16 November 2020 | url=https://www.businesswire.com/news/home/20201116005378/en/ | access-date=17 June 2024}}</ref><ref>{{cite web | title=Dilantin | website=Pfizer | url=https://www.pfizer.com/products/product-detail/dilantin | access-date=17 June 2024}}</ref><ref>{{cite web | title=Brands | website=Viatris | date=16 November 2020 | url=https://www.viatris.com/en/products/brands | access-date=17 June 2024}}</ref>

==Research==
Tentative evidence suggests that topical phenytoin is useful in wound healing in people with chronic skin wounds.<ref>{{cite journal | vauthors = Shaw J, Hughes CM, Lagan KM, Bell PM | title = The clinical effect of topical phenytoin on wound healing: a systematic review | journal = The British Journal of Dermatology | volume = 157 | issue = 5 | pages = 997–1004 | date = November 2007 | pmid = 17854378 | doi = 10.1111/j.1365-2133.2007.08160.x | s2cid = 23862219 }}</ref><ref>{{cite journal | vauthors = Bhatia A, Prakash S | title = Topical phenytoin for wound healing | journal = Dermatology Online Journal | volume = 10 | issue = 1 | pages = 5 | date = July 2004 | pmid = 15347487 | doi = 10.5070/D30Z3612W1 }}</ref> A meta-analysis also supported the use of phenytoin in managing various ulcers.<ref>{{cite journal| vauthors = Thangaraju P, Tamilselvan T, Venkatesan S, Eswaran T, Singh H, Giri VC, Ali MS |title=Topical Phenytoin for Managing Various Ulcers:A meta-analysis |journal= Sudan Medical Monitor |date= July 2015 |volume=10|issue=2|pages=63–67 |doi=10.4103/1858-5000.160951|s2cid=74076946 |doi-access=free }}</ref> Phenytoin is incorporated into compounded medications to optimize wound treatment, often in combination with [[misoprostol]].<ref>{{cite journal | vauthors = Riepl M | title = A Compendium of Compounding Agents and Formulations, Part 6: Additional Preparations for Refractory Dermal-wound Healing | journal = International Journal of Pharmaceutical Compounding | volume = 26 | issue = 6 | pages = 480–488 | date = 2022 | pmid = 36445767 | url = https://pubmed.ncbi.nlm.nih.gov/36445767/ }}</ref><ref>{{Cite journal | vauthors = Banov D, Song G, Foraida Z, Tkachova O, Zdoryk O, Carvalho M |title=Integrated In Vivo and In Vitro Evaluation of a Powder-to-Hydrogel, Film-Forming Polymer Complex Base with Tissue-Protective and Microbiome-Supportive Properties |journal=Gels |date=2024 |language=en |volume=10 |issue=7 |pages=447 |doi=10.3390/gels10070447 |doi-access=free |pmid=39057470 |pmc=11276563 |issn=2310-2861}}</ref>

Some clinical trials have explored whether phenytoin can be used as [[Neuroprotection|neuroprotector]] in [[multiple sclerosis]].<ref name="Raftopoulos_2016">{{cite journal | vauthors = Raftopoulos R, Hickman SJ, Toosy A, Sharrack B, Mallik S, Paling D, Altmann DR, Yiannakas MC, Malladi P, Sheridan R, Sarrigiannis PG, Hoggard N, Koltzenburg M, Gandini Wheeler-Kingshott CA, Schmierer K, Giovannoni G, Miller DH, Kapoor R | title = Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial | journal = The Lancet. Neurology | volume = 15 | issue = 3 | pages = 259–269 | date = March 2016 | pmid = 26822749 | doi = 10.1016/S1474-4422(16)00004-1 | s2cid = 38835886 | doi-access = free }}</ref>

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite book | vauthors=Dean L, Kane M | chapter=Phenytoin Therapy and HLA-B*15:02 and CYP2C9 Genotypes | veditors = Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | title=Medical Genetics Summaries | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK385287/ | publisher=[[National Center for Biotechnology Information]] (NCBI) | year=2016 | pmid=28520374 | id=Bookshelf ID: NBK385287 | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }}
{{refend}}

== External links ==
* [http://www.mjlphd.net/translations.html English translation of 1908 German article on phenytoin synthesis by Heinrich Biltz] {{Webarchive|url=https://web.archive.org/web/20201018004942/https://www.mjlphd.net/translations.html |date=18 October 2020 }}

{{Anticonvulsants}}
{{Antiarrhythmic agents}}
{{Navboxes
| title = [[Pharmacodynamics]]
| titlestyle = background:#ccccff
| list1 =
{{Estrogen receptor modulators}}
{{GABAA receptor modulators}}
{{Ion channel modulators}}
{{Sigma receptor modulators}}
{{Xenobiotic-sensing receptor modulators}}
}}
{{Portal bar|Medicine}}

[[Category:CYP1A2 inducers]]
[[Category:Antiarrhythmic agents]]
[[Category:Anticonvulsants]]
[[Category:Aromatase inhibitors]]
[[Category:CYP3A4 inducers]]
[[Category:Dermatoxins]]
[[Category:GABAA receptor positive allosteric modulators]]
[[Category:Hepatotoxins]]
[[Category:Hydantoins]]
[[Category:IARC Group 2B carcinogens]]
[[Category:Nephrotoxins]]
[[Category:Phenyl compounds]]
[[Category:Selective estrogen receptor modulators]]
[[Category:Sigma receptor modulators]]
[[Category:Sodium channel blockers]]
[[Category:Teratogens]]
[[Category:World Health Organization essential medicines]]
[[Category:Wikipedia medicine articles ready to translate]]