{{Short description|Medication}} {{About||the isomer of tretinoin used primarily to treat more severe acne|Isotretinoin|all-trans-retinoic acid as the metabolite of vitamin A|Retinoic acid}} {{Use dmy dates|date=December 2024}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | Watchedfields = changed | verifiedrevid = 470612798 | image = Tretinoin structure.svg | image_class = skin-invert-image | width = 275 | alt = | caption =
<!-- Clinical data --> | pronounce = See pronunciation note | tradename = Retin-A, Avita, Renova, others | Drugs.com = {{drugs.com|monograph|tretinoin}}<br />Topical {{Drugs.com|monograph|tretinoin-topical}} | MedlinePlus = a608032 | DailyMedID = Tretinoin | pregnancy_AU = X | pregnancy_AU_comment = / (Oral); D (Topical)<ref name="Drugs.com oral pregnancy">{{cite web | date = 25 July 2019 | title = Tretinoin (Vesanoid) Use During Pregnancy | website = Drugs.com | url = https://www.drugs.com/pregnancy/tretinoin.html | access-date = 16 January 2020 }}</ref><ref name="Drugs.com topical pregnancy">{{cite web | date = 1 July 2019 | title = Tretinoin topical Use During Pregnancy | website = Drugs.com | url = https://www.drugs.com/pregnancy/tretinoin-topical.html | access-date = 16 January 2020 }}</ref> | pregnancy_category= | routes_of_administration = Topical, by mouth | class = | ATC_prefix = D10 | ATC_suffix = AD01 | ATC_supplemental = {{ATC|L01|XF01}}, {{ATC|D10|AD51}}
<!-- Legal status --> | legal_AU = S4 | legal_AU_comment = | legal_BR = C2 | legal_BR_comment = <ref>{{cite web | author = Anvisa | date = 31 March 2023 | title = RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial | language = pt-BR | publisher = Diário Oficial da União | url = https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 | access-date = 15 August 2023 | archive-date = 3 August 2023 | 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 | author-link = Brazilian Health Regulatory Agency | trans-title = Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control | url-status = live | publication-date = 4 April 2023 }}</ref> | legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_CA_comment = | legal_DE = <!-- Anlage I, II, III or Unscheduled--> | legal_DE_comment = | legal_NZ = <!-- Class A, B, C --> | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="OralLabel" /><ref name="TopicalLabel" /> | legal_EU = Rx-only | legal_EU_comment = <ref>{{cite web | date = 1 December 2022 | title = List of nationally authorised medicinal products:Active substance(s): tretinoin (oral formulations) | website = ema.europa.eu | publisher = European Medicines Agency | url = https://www.ema.europa.eu/en/documents/psusa/tretinoin-oral-formulations-list-nationally-authorised-medicinal-products-psusa/00003015/202203_en.pdf | archive-date = 30 January 2023 | archive-url = https://web.archive.org/web/20230130131600/https://www.ema.europa.eu/en/documents/psusa/tretinoin-oral-formulations-list-nationally-authorised-medicinal-products-psusa/00003015/202203_en.pdf | url-status = live }}</ref> | legal_UN = <!-- N I, II, III, IV / P I, II, III, IV--> | legal_UN_comment = | legal_status = <!--For countries not listed above-->
<!-- Pharmacokinetic data --> | bioavailability = | protein_bound = > 95% | metabolism = | metabolites = | onset = | elimination_half-life = 0.5–2 hours | duration_of_action = | excretion =
<!-- Identifiers --> | CAS_number_Ref = {{cascite|correct|cas}} | CAS_number = 302-79-4 | CAS_supplemental = | PubChem = 444795 | IUPHAR_ligand = 2644 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00755 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 392618 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 5688UTC01R | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00094 | KEGG2_Ref = {{keggcite|correct|kegg}} | KEGG2 = C00777 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 15367 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 38 | NIAID_ChemDB = | PDB_ligand = | synonyms = ATRA
<!-- Chemical and physical data --> | IUPAC_name = (2''E'',4''E'',6''E'',8''E'')-3,7-Dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid | C=20 | H=28 | O=2 | SMILES = CC1=C(C(CCC1)(C)C)C=CC(=CC=CC(=CC(=O)O)C)C | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C20H28O2/c1-15(8-6-9-16(2)14-19(21)22)11-12-18-17(3)10-7-13-20(18,4)5/h6,8-9,11-12,14H,7,10,13H2,1-5H3,(H,21,22)/b9-6+,12-11+,15-8+,16-14+ | StdInChI_comment = | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} Arsen Ramirez Cruzﺁ | StdInChIKey = SHGAZHPCJJPHSC-YCNIQYBTSA-N dd><htt//60967409 | density = | density_notes = | melting_point = 180 | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}
<!-- Definition and medical uses --> '''Tretinoin''', also known as '''all-''trans'' retinoic acid''' ('''ATRA'''), is a medication used for the treatment of acne and acute promyelocytic leukemia.<ref name="AHFS2016" /><ref name="Tiv2016">{{cite book | vauthors = Tivnan A | date = 2016 | title = Resistance to Targeted Therapies Against Adult Brain Cancers | publisher = Springer | page = 123 | isbn = 978-3-319-46505-0 | url = https://books.google.com/books?id=XaCYDQAAQBAJ&pg=PA123 | archive-date = 5 November 2017 | archive-url = https://web.archive.org/web/20171105200032/https://books.google.ca/books?id=XaCYDQAAQBAJ&pg=PA123 | url-status = live }}</ref><ref name="BNF69">{{cite book | date = 2015 | title = British national formulary: BNF 69 | publisher = British Medical Association | edition = 69 | pages = 627, 821–822 | isbn = 978-0-85711-156-2 }}</ref> For acne, it is applied to the skin as a cream, gel or ointment.<ref name="BNF69" /> For acute promyelocytic leukemia, it is effective only when the RARA-PML fusion mutation is present<ref>{{cite journal | vauthors = Yoshida H, Kitamura K, Tanaka K, Omura S, Miyazaki T, Hachiya T, Ohno R, Naoe T | date = July 1996 | title = Accelerated degradation of PML-retinoic acid receptor alpha (PML-RARA) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: possible role of the proteasome pathway | journal = Cancer Research | volume = 56 | issue = 13 | pages = 2945–2948 | pmid = 8674046 }}</ref> and is taken by mouth for up to three months.<ref name="AHFS2016">{{cite web | title = Tretinoin | publisher = The American Society of Health-System Pharmacists | url = https://www.drugs.com/monograph/tretinoin.html | access-date = 8 December 2016 | archive-date = 30 November 2016 | archive-url = https://web.archive.org/web/20161130124932/https://www.drugs.com/monograph/tretinoin.html | url-status = live }}</ref> Topical tretinoin is also the most extensively investigated retinoid therapy for photoaging.<ref>{{cite web | title = Retinoids, topical | publisher = American Osteopathic College of Dermatology | url = https://www.aocd.org/page/Retinoidstopical }}</ref>
<!-- Side effects and mechanism --> Common side effects when used as a cream are limited to the skin and include skin redness, peeling, and sun sensitivity.<ref name="BNF69" /> When taken by mouth, side effects include hypertriglyceridemia, hypercholesterolemia, shortness of breath, headache, numbness, depression, skin dryness, itchiness, hair loss, vomiting, muscle pains, and vision changes.<ref name="AHFS2016" /> Other severe side effects include high white blood cell counts and blood clots.<ref name="AHFS2016" /> Use during pregnancy is contraindicated due to the risk of birth defects.<ref name="AHFS2016" /><ref name="Drugs.com oral pregnancy" /> It is in the retinoid family of medications.<ref name="Tiv2016" />
<!-- History and culture --> Tretinoin was patented in 1957 and approved for medical use in 1962.<ref name="Fis2006">{{cite book | vauthors = Fischer J, Ganellin CR | date = 2006 | title = Analogue-based Drug Discovery | publisher = John Wiley & Sons | page = 476 | isbn = 978-3-527-60749-5 | url = https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA476 | archive-date = 5 November 2017 | archive-url = https://web.archive.org/web/20171105200032/https://books.google.ca/books?id=FjKfqkaKkAAC&pg=PA476 | url-status = live }}</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | year = 2019 | title = World Health Organization model list of essential medicines: 21st list 2019 | publisher = World Health Organization | hdl = 10665/325771 | author-link = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access = free }}</ref> Tretinoin is available as a generic medication.<ref name="AHFS2016B">{{cite web | title = Tretinoin topical | publisher = The American Society of Health-System Pharmacists | url = https://www.drugs.com/monograph/tretinoin-topical.html | access-date = 8 December 2016 | archive-date = 16 May 2016 | archive-url = https://web.archive.org/web/20160516200244/http://www.drugs.com/monograph/tretinoin-topical.html | url-status = live }}</ref> In 2023, it was the 197th most commonly prescribed medication in the United States, with more than two million prescriptions.<ref name="Top 300">{{cite web | title = Top 300 of 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Top300Drugs.aspx | access-date = 12 August 2025 | archive-date = 12 August 2025 | archive-url = https://web.archive.org/web/20250812130026/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status = live }}</ref><ref>{{cite web | title = Tretinoin Drug Usage Statistics, United States, 2014 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Tretinoin | access-date = 20 August 2025 }}</ref>
== Medical uses ==
=== Skin use === ==== Acne ==== Tretinoin is most commonly used to treat acne<ref name="TopicalLabel" /> both non-inflammatory, such as comedonal acne, and inflammatory, such as acne vulgaris.<ref>{{cite web | title = What Is Tretinoin? Skin-Care Benefits, Side Effects, How to Use It, and More | website = everydayhealth.com | url = https://www.everydayhealth.com/healthy-skin/tretinoin/guide/ | access-date = 2026-03-07 }}</ref> It's effective across a diverse patient population, including those of darker skin tones, and has been shown to significantly lighten postinflammatory hyperpigmented lesions in Black patients.<ref name=":0">{{cite journal | vauthors = Bulengo-Ransby SM, Griffiths CE, Kimbrough-Green CK, Finkel LJ, Hamilton TA, Ellis CN, Voorhees JJ | date = May 1993 | title = Topical tretinoin (retinoic acid) therapy for hyperpigmented lesions caused by inflammation of the skin in black patients | journal = The New England Journal of Medicine | volume = 328 | issue = 20 | pages = 1438–1443 | doi = 10.1056/NEJM199305203282002 | pmid = 8479462 }}</ref> Multiple studies support the efficacy of topical retinoids in the treatment of acne vulgaris.<ref>{{cite journal | vauthors = Leyden JJ, Shalita A, Thiboutot D, Washenik K, Webster G | date = February 2005 | title = Topical retinoids in inflammatory acne: a retrospective, investigator-blinded, vehicle-controlled, photographic assessment | journal = Clinical Therapeutics | volume = 27 | issue = 2 | pages = 216–224 | doi = 10.1016/j.clinthera.2005.02.009 | pmid = 15811485 }}</ref><ref>{{cite journal | vauthors = Webster G, Cargill DI, Quiring J, Vogelson CT, Slade HB | date = March 2009 | title = A combined analysis of 2 randomized clinical studies of tretinoin gel 0.05% for the treatment of acne | journal = Cutis | volume = 83 | issue = 3 | pages = 146–154 | pmid = 19363908 }}</ref> It is sometimes used in conjunction with other topical acne medications to enhance their penetration.<ref name="pmid12833004">{{cite journal | vauthors = Gollnick H, Cunliffe W, Berson D, Dreno B, Finlay A, Leyden JJ, Shalita AR, Thiboutot D | date = July 2003 | title = Management of acne: a report from a Global Alliance to Improve Outcomes in Acne | journal = Journal of the American Academy of Dermatology | volume = 49 | issue = 1 Suppl | article-number = S1-37 | doi = 10.1067/mjd.2003.618 | pmid = 12833004 | collaboration = Global Alliance to Improve Outcomes in Acne }}</ref> In addition to treating active acne, retinoids accelerate the resolution of acne-induced postinflammatory hyperpigmentation.<ref name="Kang S 2008">{{cite book | vauthors = Kang S, Voorhees JJ | date = 2008 | veditors = Wolff K, Goldsmith LA, Katz SI, etal | chapter = Topical retinoids. | title = Fitzpatrick's Dermatology in General Medicine | publisher = McGraw Hill | edition = 7th | page = 2106 | location = New York }}</ref> It is also useful as maintenance therapy for people who have responded well to their initial treatment, reducing the prolonged use of antibiotics for acne.<ref>{{cite journal | vauthors = Leyden J, Stein-Gold L, Weiss J | date = September 2017 | title = Why Topical Retinoids Are Mainstay of Therapy for Acne | journal = Dermatology and Therapy | volume = 7 | issue = 3 | pages = 293–304 | doi = 10.1007/s13555-017-0185-2 | pmc = 5574737 | pmid = 28585191 }}</ref>Lotion-based tretinoin formulations have been developed to improve tolerability while maintaining efficacy in acne treatment.<ref name=":1">{{cite journal | vauthors = Cook-Bolden FE, Weinkle SH, Guenin E, Bhatt V | date = January 2019 | title = Novel Tretinoin 0.05% Lotion for Once-Daily Treatment of Moderate-to-Severe Acne Vulgaris in a Hispanic Population | journal = Journal of Drugs in Dermatology | volume = 18 | issue = 1 | pages = 32–38 | pmid = 30681791 }}</ref>
==== Photoaging ==== Photoaging is premature skin aging resulting from prolonged and repeated exposure to solar radiation. Features of photoaging include fine and coarse wrinkles, changes in skin pigmentation, and loss of elasticity. In human skin, topical retinoids increase collagen production, induce epidermal hyperplasia, and decrease keratinocyte and melanocyte atypia. Topical tretinoin is the most extensively investigated retinoid therapy for photoaging.<ref>{{cite journal | vauthors = Han A, Chien AL, Kang S | date = July 2014 | title = Photoaging | journal = Dermatologic Clinics | volume = 32 | issue = 3 | article-number = 291–9, vii | doi = 10.1016/j.det.2014.03.015 | pmid = 24891052 }}</ref> Topical tretinoin can be used for mild to severe photoaging in people of all skin types. Several weeks or months of use are typically required before improvement is appreciated. Although it has only been studied for up to two years, it may be continued indefinitely. A long-term maintenance regimen with a lower concentration or less frequent application may be an alternative to continued use.<ref>{{cite journal | vauthors = Kang S, Bergfeld W, Gottlieb AB, Hickman J, Humeniuk J, Kempers S, Lebwohl M, Lowe N, McMichael A, Milbauer J, Phillips T, Powers J, Rodriguez D, Savin R, Shavin J, Sherer D, Silvis N, Weinstein R, Weiss J, Hammerberg C, Fisher GJ, Nighland M, Grossman R, Nyirady J | date = 2005 | title = Long-term efficacy and safety of tretinoin emollient cream 0.05% in the treatment of photodamaged facial skin: a two-year, randomized, placebo-controlled trial | journal = American Journal of Clinical Dermatology | volume = 6 | issue = 4 | pages = 245–253 | doi = 10.2165/00128071-200506040-00005 | pmid = 16060712 | s2cid = 40127961 }}</ref>
==== Available forms ==== Topical tretinoin is available in several formulations, including creams, gels, microsphere gels, and lotions.<ref name="Ishver">{{cite web | vauthors = Ishver A | date = 7 October 2024 | title = Tretinoin topical (Retin-A, Renova, and others) | website = WebMD | url = https://www.webmd.com/drugs/2/drug-3956/tretinoin-topical/details | access-date = 2 April 2025 }}</ref>
Lotion-based formulations of Tretinoin, such as 0.05% tretinoin lotion, were developed from polymeric emulsion technology to improve the skin's tolerability while maintaining clinical efficacy. Clinical trials demonstrated these lotions significantly reduce both inflammatory and non-inflammatory acne lesions.<ref>{{cite journal | vauthors = Lain E, Day D, Harper J, Guenin E | date = November 2019 | title = Tretinoin 0.05% Lotion for the Once-Daily Treatment of Moderate-to-Severe Acne Vulgaris: Impact of Gender and Race on Efficacy and Safety | journal = Journal of Drugs in Dermatology | volume = 18 | issue = 11 | pages = 1128–1138 | pmid = 31741356 }}</ref> These formulations were generally well tolerated with the most common side effect being skin dryness. The formulations were significant in reducing acne lesions among diverse patient demographics and sexes, including Hispanic and Black patients.<ref name=":1" /><ref name=":0" />
The chemical stability of tretinoin is significantly affected by light and oxidizing agents. When combined with 10% benzoyl peroxide and exposed to light, significant degradation occurs, with over 50% of the compound degrading within approximately two hours and up to 95% within 24 hours.<ref name="Wiley 1998 pp. 8–11">{{cite journal | vauthors = Martin B, Meunier C, Montels D, Watts O | date = October 1998 | title = Chemical stability of adapalene and tretinoin when combined with benzoyl peroxide in presence and in absence of visible light and ultraviolet radiation | journal = The British Journal of Dermatology | publisher = Wiley | volume = 139 | issue = Suppl 52 | pages = 8–11 | doi = 10.1046/j.1365-2133.1998.1390s2008.x | pmid = 9990414 | s2cid = 43287596 }}</ref>
To address this instability, alternative formulations have been developed. The microsphere gel formulation utilizes microsponge technology, encapsulating tretinoin within an aqueous gel matrix to enhance stability and control the release of the active ingredient.<ref name="pmid17243432">{{cite journal | vauthors = Weiss JS, Shavin JS, Nighland M, Grossman R | date = December 2006 | title = Tretinoin microsphere gel 0.1% for photodamaged facial skin: a placebo-controlled trial | journal = Cutis | volume = 78 | issue = 6 | pages = 426–432 | pmid = 17243432 }}</ref><ref name="Osmani 2014">{{cite journal | vauthors = Osmani RA, Aloorkar NH, Kulkarni AS, Harkare BR, Bhosale RR | date = March 2014 | title = A new cornucopia in topical drug delivery: Microsponge technology | journal = Asian Journal of Pharmaceutical Science & Technology | volume = 4 | issue = 1 | pages = 48–60 | url = https://www.researchgate.net/publication/261873915 | access-date = January 15, 2026 }}</ref> When microsponge tretinoin is exposed to benzoyl peroxide and light, it exhibits improved stability compared to other formulations, with only approximately 1% degradation after four hours and approximately 13% after 24 hours.<ref name="pmid12469785">{{cite journal | vauthors = Nyirady J, Lucas C, Yusuf M, Mignone P, Wisniewski S | date = November 2002 | title = The stability of tretinoin in tretinoin gel microsphere 0.1% | journal = Cutis | volume = 70 | issue = 5 | pages = 295–298 | pmid = 12469785 | url = https://www.mdedge.com/dermatology/article/66872/acne/stability-tretinoin-tretinoin-gel-microsphere-01 }}</ref><ref name="Osmani 2014"/> In addition to the use of microsponges for stabilization, certain microencapsulation formulations of tretinoin/benzoyl peroxide utilize a silica-based sol-gel technology to combine these ingredients without damaging the tretinoin. These amorphous silica shells physically separate the active agents to prevent degradation, while both systems work to regulate delivery into the skin to enhance shelf life and patient tolerability.<ref name="pmid37792034">{{cite journal | vauthors = Green LJ, Bhatia ND, Toledano O, Erlich M, Spizuoco A, Goodyear BC, York JP, Jakus J | date = December 2023 | title = Silica-based microencapsulation used in topical dermatologic applications | journal = Archives of Dermatological Research | volume = 315 | issue = 10 | pages = 2787–2793 | doi = 10.1007/s00403-023-02725-z | pmc = 10616207 | pmid = 37792034 }}</ref>
=== Leukemia === Tretinoin is used to induce remission in people with acute promyelocytic leukemia (APL) who have a mutation (the t(15;17) translocation that gives rise to the PML::RARα fusion gene). It is not used for maintenance therapy.<ref name="OralLabel">{{cite web | date = 12 December 2018 | title = Tretinoin capsule | website = DailyMed | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=264138c1-9e5f-45ef-be87-79ca97c989d9 | access-date = 16 January 2020 }}</ref><ref>{{cite journal | vauthors = Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, Gu LJ, Wang ZY | date = August 1988 | title = Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia | journal = Blood | volume = 72 | issue = 2 | pages = 567–572 | doi = 10.1182/blood.V72.2.567.567 | pmid = 3165295 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Castaigne S, Chomienne C, Daniel MT, Ballerini P, Berger R, Fenaux P, Degos L | date = November 1990 | title = All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results | journal = Blood | volume = 76 | issue = 9 | pages = 1704–1709 | doi = 10.1182/blood.V76.9.1704.1704 | pmid = 2224119 | doi-access = free }}</ref>
Tretinoin is not effective for the treatment of non-APL forms of acute myeloid leukemia<ref>{{cite journal | vauthors = Küley-Bagheri Y, Kreuzer KA, Monsef I, Lübbert M, Skoetz N | date = August 2018 | title = Effects of all-trans retinoic acid (ATRA) in addition to chemotherapy for adults with acute myeloid leukaemia (AML) (non-acute promyelocytic leukaemia (non-APL)) | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | issue = 8 | article-number = CD011960 | doi = 10.1002/14651858.CD011960.pub2 | pmc = 6513628 | pmid = 30080246 | collaboration = Cochrane Haematological Malignancies Group }}</ref> or other forms of leukemia. Preclinical studies and clinical data analysis suggest that retinoic acid promotes the growth of T-cell acute lymphoblastic leukemia.<ref>{{cite journal | vauthors = Ono Y, Fukuhara N, Yoshie O | date = December 1998 | title = TAL1 and LIM-only proteins synergistically induce retinaldehyde dehydrogenase 2 expression in T-cell acute lymphoblastic leukemia by acting as cofactors for GATA3 | journal = Molecular and Cellular Biology | volume = 18 | issue = 12 | pages = 6939–6950 | doi = 10.1128/MCB.18.12.6939 | pmc = 109277 | pmid = 9819382 }}</ref>
== Side effects ==
=== Dermatology === Topical tretinoin is for use only on the skin and should not be applied to eyes or mucosal tissues. Common side effects include skin irritation, redness, swelling, and blistering.<ref name="TopicalLabel">{{cite web | date = 1 December 2018 | title = Tretinoin Cream- tretinoin cream | website = DailyMed | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=745cc3ce-60b4-4479-a055-316817567949 | access-date = 16 January 2020 }}</ref> If irritation is a problem, a decrease in the frequency of application to every other or every third night can be considered, and the frequency of application can be increased as tolerance improves. The fine skin flaking that is often seen can be gently exfoliated with a washcloth. A non-comedogenic facial moisturizer can also be applied if needed. Delaying the application of the retinoid for at least 20 minutes after washing and drying the face may also be helpful. Topical retinoids are not true photosensitizing drugs, but people using topical retinoids have described symptoms of increased sun sensitivity. This is thought to be due to the thinning of the stratum corneum leading to a decreased barrier against ultraviolet light exposure, as well as an enhanced sensitivity due to the presence of cutaneous irritation.<ref>{{cite journal | vauthors = Zaenglein AL | date = September 2008 | title = Topical retinoids in the treatment of acne vulgaris | journal = Seminars in Cutaneous Medicine and Surgery | volume = 27 | issue = 3 | pages = 177–182 | doi = 10.1016/j.sder.2008.06.001 | pmid = 18786495 | doi-broken-date = 12 April 2026 }}</ref>
=== Acute promyelocytic leukemia === The oral form of the drug has boxed warnings concerning the risks of retinoic acid syndrome and leukocytosis.<ref name="OralLabel" /> Other significant side effects include a risk of thrombosis, benign intracranial hypertension in children, high lipids (hypercholesterolemia and/or hypertriglyceridemia), and liver damage.<ref name="OralLabel" />
There are many significant side effects from this drug that include malaise (66%), shivering (63%), hemorrhage (60%), infections (58%), peripheral edema (52%), pain (37%), chest discomfort (32%), edema (29%), disseminated intravascular coagulation (26%), weight increase (23%), injection site reactions (17%), anorexia (17%), weight decrease (17%), and myalgia (14%).<ref name="OralLabel" />
Respiratory side effects usually signify retinoic acid syndrome (also called differentiation syndrome), and include upper respiratory tract disorders (63%), dyspnea (60%), respiratory insufficiency (26%), pleural effusion (20%), pneumonia (14%), rales (14%), and expiratory wheezing (14%), and many others at less than 10%.<ref name="OralLabel" /> Around 23% of people taking the drug have reported earache or a feeling of fullness in their ears.<ref name="OralLabel" /> Gastrointestinal disorders include bleeding (34%), abdominal pain (31%), diarrhea (23%), constipation (17%), dyspepsia (14%), and swollen belly (11%) and many others at less than 10%.<ref name="OralLabel" />
Cardiovascular side effects include arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%), phlebitis (11%), and cardiac failure (6%) and for 3% of patients: cardiac arrest, myocardial infarction, enlarged heart, heart murmur, ischemia, stroke, myocarditis, pericarditis, pulmonary hypertension, secondary cardiomyopathy.<ref name="OralLabel" />
In the nervous system, side effects include dizziness (20%), paresthesias (17%), anxiety (17%), insomnia (14%), depression (14%), confusion (11%), and many others at less than 10% frequency.<ref name="OralLabel" />
In the urinary system, side effects include chronic kidney disease (11%) and several others at less than 10% frequency.<ref name="OralLabel" />
== Mechanism of action == thumb|Effects of topical tretinoin on skin For its use in acute promyelocytic leukemia, tretinoin causes the RARA:PML fusion oncogene to degrade, resulting in the loss of the key driver oncogene.<ref>{{cite journal | vauthors = Yoshida H, Kitamura K, Tanaka K, Omura S, Miyazaki T, Hachiya T, Ohno R, Naoe T | date = July 1996 | title = Accelerated degradation of PML-retinoic acid receptor alpha (PML-RARA) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: possible role of the proteasome pathway | journal = Cancer Research | volume = 56 | issue = 13 | pages = 2945–2948 | pmid = 8674046 }}</ref> This degradation allows the blasts to mature and results in dramatic responses. This response is typically short-lived as CYP26 genes are rapidly upregulated to degrade tretinoin. The RARA:PML oncogene is not present in other cancer types, thus explaining why tretinoin and other retinoids have not been effective across hundreds of different trials.<ref>{{cite journal | vauthors = Esposito M, Amory JK, Kang Y | date = September 2024 | title = The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes | journal = The Journal of Experimental Medicine | volume = 221 | issue = 9 | article-number = e20240519 | doi = 10.1084/jem.20240519 | pmc = 11318670 | pmid = 39133222 | doi-access = free }}</ref>
For its use in acne, tretinoin (along with other retinoids) are vitamin A derivatives that act by binding to two nuclear receptor families within keratinocytes: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR).<ref name="Kang S 2008" /> These events contribute to the normalization of follicular keratinization and decreased cohesiveness of keratinocytes, resulting in reduced follicular occlusion and microcomedone formation.<ref>Fernandez [Graber] EM, Zaenglein A, Thiboutot D. Acne Treatment Methodologies. In: Cosmetic Formulation of Skin Care Products, Taylor and Francis Group, New York 2006. p.273.</ref> The retinoid-receptor complex competes for coactivator proteins of AP-1, a key transcription factor involved in inflammation.<ref name="Kang S 2008" /> Retinoids also down-regulate expression of toll-like receptor (TLR)-2, which has been implicated in the inflammatory response in acne.<ref>{{cite journal | vauthors = Liu PT, Krutzik SR, Kim J, Modlin RL | date = March 2005 | title = Cutting edge: all-trans retinoic acid down-regulates TLR2 expression and function | journal = Journal of Immunology | volume = 174 | issue = 5 | pages = 2467–2470 | doi = 10.4049/jimmunol.174.5.2467 | pmid = 15728448 | s2cid = 20740543 | doi-access = free }}</ref> Moreover, tretinoin and retinoids may enhance the penetration of other topical acne medications.<ref name="pmid12833004" />
The biological mechanism behind triglyceride and cholesterol elevations remains under investigation.<ref>{{cite journal | vauthors = Jo SH | date = September 2025 | title = Triglycerides, Triglyceride-Rich Lipoproteins, and Remnant Cholesterol in Atherosclerotic Cardiovascular Disease | journal = Journal of Lipid and Atherosclerosis | volume = 14 | issue = 3 | pages = 247–257 | doi = 10.12997/jla.2025.14.3.247 | pmc = 12488791 | pmid = 41048608 }}</ref>
== Synthesis == class=skin-invert-image|thumb|Biosynthetic pathway of tretinon All-trans retinoic acid is produced by the body from dietary factors including retinol, retinyl esters or beta-carotene. The beta-carotene is first cleaved by beta-carotene 15-15'-monooxygenase to retinol which is subsequently oxidized by RDH and ALDH enzymes to produce all-trans retinoic acid (see retinoic acid). Tretinoin is produced synthetically using standard industrial practices.<ref>{{cite web | title = WIPO - Search International and National Patent Collections | website = patentscope.wipo.int | url = https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012155796 | access-date = 15 August 2024 }}</ref>
== History == Tretinoin was initially patented in 1957 and received approval for clinical use in 1962.<ref name="Fis2006"/> Its application as an acne treatment was co-developed by James Fulton and Albert Kligman at the University of Pennsylvania in the 1960s.<ref name="FultonObit">{{cite web | date = 10 July 2013 | title = Vivant Skin Care Co-founder James E. Fulton, MD, Loses Colon Cancer Battle | work = Vivant Pharmaceuticals, LLC Press Release | url = http://vivantskin.blogspot.com/2013/07/vivant-skin-care-co-founder-james-e.html | archive-date = 18 April 2016 | archive-url = https://web.archive.org/web/20160418081737/http://vivantskin.blogspot.com/2013/07/vivant-skin-care-co-founder-james-e.html }}</ref><ref name="KligmanObit">{{cite web | vauthors = Gellene D | date = 22 February 2010 | title = Dr. Albert M. Kligman, Dermatologist, Dies at 93 | work = The New York Times | url = https://www.nytimes.com/2010/02/23/us/23kligman.html?_r=0 }}</ref><ref name="Kelly 2025">{{cite web | vauthors = Kelly K | date = 26 February 2025 | title = The Horrifying History Behind a Beloved Skin-Care Ingredient | website = Teen Vogue | url = https://www.teenvogue.com/story/retinol-skincare-ingredient-history | access-date = 8 April 2025 }}</ref> Phase I trials, the first conducted on human subjects, were performed on inmates at Holmesburg Prison during a long-running regime of non-therapeutic testing on prison inmates at Holmesburg.<ref name="Kelly 2025"/><ref>{{cite book | vauthors = Washington HA | date = 2006 | title = Medical apartheid: the dark history of medical experimentation on Black Americans from colonial times to the present | publisher = Doubleday | isbn = 978-0-385-50993-0 | location = New York | oclc = 61131882 }}</ref><ref>{{cite book | vauthors = Hornblum AM | date = 1998 | title = Acres of skin: human experiments at Holmesburg Prison: a story of abuse and exploitation in the name of medical science | publisher = Routledge | isbn = 978-0-415-91990-6 | location = New York | oclc = 37884781 }}</ref> The University of Pennsylvania held the patent for Retin-A, which it subsequently licensed to various pharmaceutical companies,<ref name="KligmanObit" /> and the compound received US Food and Drug Administration (FDA) approval for acne in 1971.<ref name="Kelly 2025"/><ref name="pmid33871811">{{cite journal | vauthors = Baldwin H, Webster G, Stein Gold L, Callender V, Cook-Bolden FE, Guenin E | date = May 2021 | title = 50 Years of Topical Retinoids for Acne: Evolution of Treatment | journal = American Journal of Clinical Dermatology | volume = 22 | issue = 3 | pages = 315–327 | doi = 10.1007/s40257-021-00594-8 | pmid = 33871811 }}</ref>
Treatment of acute promyelocytic leukemia was first introduced at Ruijin Hospital in Shanghai by Wang Zhenyi in a 1988 clinical trial.<ref>{{cite journal | vauthors = Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, Gu LJ, Wang ZY | date = August 1988 | title = Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia | journal = Blood | volume = 72 | issue = 2 | pages = 567–572 | doi = 10.1182/blood.V72.2.567.567 | pmid = 3165295 | doi-access = free }}</ref>
In 1997, the FDA approved tretinoin microsphere gel, marketed as Retin-A Micro, for the treatment of acne.<ref name="pmid17243432"/>
== Etymology == The origin of the name ''tretinoin'' is uncertain,<ref name="MW_Medical" /><ref name="OxfordDictionaries">{{Citation| title = Tretinoin |work = Oxford Dictionaries Online |publisher=Oxford University Press |url=https://www.oxfordreference.com/display/10.1093/oi/authority.20110803105624146 }}</ref> although several sources agree (one with probability,<ref name="MW_Medical" /> one with asserted certainty<ref name="AHD">{{Citation |author=Houghton Mifflin Harcourt |title=The American Heritage Dictionary of the English Language |publisher=Houghton Mifflin Harcourt |url=https://ahdictionary.com/ |postscript=. |archive-url=https://web.archive.org/web/20150925104737/https://ahdictionary.com/ |archive-date=25 September 2015 |access-date=24 January 2015}}</ref>) that it probably comes from ''trans-'' + ''retinoic [acid]'' + ''-in'', which is plausible given that tretinoin is the all-trans isomer of retinoic acid. The name ''isotretinoin'' is the same root ''tretinoin'' plus the prefix ''iso-''. Regarding pronunciation, the following variants apply equally to both ''tretinoin'' and ''isotretinoin''. Given that ''retinoic'' is pronounced {{IPAc-en|ˌ|r|ɛ|t|ɪ|ˈ|n|oʊ|ɪ|k}},<ref name="OxfordDictionaries" /><ref name="AHD" /><ref name="MW_Medical">{{Citation |title= Tretinoin | work = Merriam-Webster's Medical Dictionary | date = 30 January 2025 |publisher=Merriam-Webster |url=https://www.merriam-webster.com/dictionary/tretinoin |postscript=.}}</ref><ref name="Dorlands">{{Citation |title=Tretinoin |work=Dorland's Illustrated Medical Dictionary |publisher=Elsevier |url=https://www.dorlandsonline.com/dorland/definition?id=50812 |postscript=. }}{{Dead link|date=June 2025 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> it is natural that {{IPAc-en|ˌ|t|r|ɛ|t|ɪ|ˈ|n|oʊ|ɪ|n}} is a commonly heard pronunciation. Dictionary transcriptions also include {{IPAc-en|ˌ|t|r|ɪ|ˈ|t|ɪ|n|oʊ|ɪ|n}} ({{respell|tri|TIN|oh|in}})<ref name="OxfordDictionaries" /><ref name="MW_Medical" /> and {{IPAc-en|ˈ|t|r|ɛ|t|ɪ|n|ɔɪ|n}}.<ref name="AHD" /><ref name="Dorlands" />
== Research == Tretinoin has been explored as a treatment for hair loss,<ref name="pmid34984080">{{cite journal | vauthors = Sattur SS, Sattur IS | date = October 2021 | title = Pharmacological Management of Pattern Hair Loss | journal = Indian Journal of Plastic Surgery | volume = 54 | issue = 4 | pages = 422–434 | doi = 10.1055/s-0041-1739254 | pmc = 8719956 | pmid = 34984080 }}</ref> potentially as a way to increase the ability of minoxidil (by acting as an enzyme and accelerating the production of minoxidil sulfate) to penetrate the scalp, but the evidence is weak and contradictory.<ref>{{cite book | vauthors = Trüeb RM | date = 2015 | chapter = Diagnosis and Treatment | title = The Difficult Hair Loss Patient: Guide to Successful Management of Alopecia and Related Conditions. | publisher = Springer | isbn = 978-3-319-19701-2 | archive-date = 5 November 2017 | archive-url = https://web.archive.org/web/20171105200032/https://books.google.com/books?id=0ue5BAAAQBAJ&pg=PA95 | location = Cham | chapter-url = https://books.google.com/books?id=0ue5BAAAQBAJ&pg=PA95 }}</ref><ref>{{cite journal | vauthors = Rogers NE, Avram MR | date = October 2008 | title = Medical treatments for male and female pattern hair loss | journal = Journal of the American Academy of Dermatology | volume = 59 | issue = 4 | article-number = 547–66; quiz 567–8 | doi = 10.1016/j.jaad.2008.07.001 | pmid = 18793935 }}</ref>
== References == {{Reflist}}
== External links == * {{cite web | title = Tretinoin Topical | website = MedlinePlus | url = https://medlineplus.gov/druginfo/meds/a682437.html }}
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