| Revision as of 11:45, 16 February 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 477032874 of page Isotretinoin for the Chem/Drugbox validation project (updated: ''). |
Latest revision as of 02:22, 10 December 2024 edit 2601:642:c303:f370:103a:b9cd:8e09:9e6 (talk) ce |
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{{Short description|Medication primarily used to treat severe acne}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}} |
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{{For|the isomer of isotretinoin primarily used topically to treat less severe acne|Tretinoin}} |
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{{drugbox| Verifiedfields = changed |
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{{Use dmy dates|date=December 2022}} |
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| verifiedrevid = 400139067 |
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{{cs1 config|name-list-style=vanc|display-authors=6}} |
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| IUPAC_name = (13''cis'')-retinoic acid |
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{{drugbox |
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| image = Isotretinoin skeletal.svg |
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| Watchedfields = changed |
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| image2 = Isotretinoína3D.png |
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| verifiedrevid = 477168707 |
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| width2 = 250 |
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| image = Isotretinoin structure.svg |
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| width = 250 |
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| alt = |
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| image2 = Isotretinoin-from-xtal-3D-bs-17.png |
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| alt2 = |
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<!--Clinical data--> |
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<!--Clinical data--> |
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| pronounce = ] |
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| tradename = Accutane |
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| tradename = Accutane, Roaccutane, ]<ref name=brands/> |
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| Drugs.com = {{drugs.com|monograph|isotretinoin}} |
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| Drugs.com = {{drugs.com|monograph|isotretinoin}} |
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| MedlinePlus = a681043 |
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| MedlinePlus = a681043 |
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| licence_US = Isotretinoin |
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| DailyMedID = Isotretinoin |
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| pregnancy_AU = X |
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| pregnancy_AU = X |
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| routes_of_administration = ], ] |
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| pregnancy_US = X |
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| ATC_prefix = D10 |
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| ATC_suffix = AD04 |
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| legal_AU = S4 |
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| legal_AU = S4 |
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| legal_AU_comment = <ref>{{cite web | url = https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=roproacc10413 | title = Product. Roaccutane PI | work = guildlink.com.au }}</ref> |
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| legal_BR = C2 |
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| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |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=2023-08-03 |access-date=2023-08-15 |publisher=] |language=pt-BR |publication-date=2023-04-04}}</ref> |
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| legal_CA = Rx-only |
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| legal_UK = POM |
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| legal_UK = POM |
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| legal_US = Rx-only |
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| legal_US = Rx-only |
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| legal_EU = Rx-only |
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| routes_of_administration = Oral, topical |
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| legal_EU_comment = <ref>{{cite web | url = https://www.ema.europa.eu/documents/psusa/isotretinoin-oral-formulations-list-nationally-authorised-medicinal-products-psusa/00010488/202205_en.pdf | title = List of nationally authorised medicinal products | work = European Medicines Agency | date = 1 December 2022 | access-date = 25 December 2022 }}</ref> |
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| legal_status = Rx-only |
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<!--Pharmacokinetic data--> |
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<!--Pharmacokinetic data--> |
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| bioavailability = Variable |
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| bioavailability = Variable |
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| protein_bound = 99.9% |
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| protein_bound = 99.9% |
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| metabolism = ] |
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| metabolism = ] |
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| elimination_half-life = 10–20 hours |
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| elimination_half-life = 10–20 hours |
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| excretion = ] and ] |
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| excretion = ] and ] |
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<!--Identifiers--> |
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<!--Identifiers--> |
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| IUPHAR_ligand = 7600 |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 4759-48-2 |
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| CAS_number = 4759-48-2 |
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| ATC_prefix = D10 |
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| ATC_suffix = AD04 |
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| PubChem = 5282379 |
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| PubChem = 5282379 |
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| DrugBank_Ref = {{drugbankcite|changed|drugbank}} |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = DB00982 |
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| DrugBank = DB00982 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = EH28UP18IF |
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| UNII = EH28UP18IF |
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| KEGG_Ref = {{keggcite|changed|kegg}} |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D00348 |
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| KEGG = D00348 |
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| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 6067 |
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| ChEBI = 6067 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 547 |
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| ChEMBL = 547 |
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<!--Chemical data--> |
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<!--Chemical data--> |
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| IUPAC_name = (2''Z'',4''E'',6''E'',8''E'')-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoic acid |
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| C=20 | H=28 | O=2 |
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| C=20 | H=28 | O=2 |
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| molecular_weight = 300.44 g/mol |
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| smiles = O=C(O)\C=C(/C=C/C=C(/C=C/C1=C(/CCCC1(C)C)C)C)C |
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| smiles = O=C(O)\C=C(/C=C/C=C(/C=C/C1=C(/CCCC1(C)C)C)C)C |
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| InChI = 1/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- |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| 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- |
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| 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- |
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| StdInChIKey = SHGAZHPCJJPHSC-XFYACQKRSA-N |
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| StdInChIKey = SHGAZHPCJJPHSC-XFYACQKRSA-N |
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}} |
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}} |
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<!-- Definition and medical uses --> |
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'''Isotretinoin''', also known as '''13-''cis''-retinoic acid''' and sold under the brand name '''Accutane''' among others, is a medication used to treat skin diseases like ], and ], and severe cystic ] or moderate acne that is unresponsive to antibiotics.<ref>{{Cite journal | vauthors = Mohiuddin AK |date=2019 |title=A Comprehensive Review of Acne Vulgaris |journal=Journal of Clinical Pharmacy |volume=1 |issue=1 |pages=17–45}}</ref> Isotretinoin is used off-label to treat ] and ], although clinical evidence suggests it is not effective in this setting.<ref>{{cite journal | vauthors = Clouser MC, Roe DJ, Foote JA, Harris RB, Alberts DS | title = Dose response of retinol and isotretinoin in the prevention of nonmelanoma skin cancer recurrence | journal = Nutrition and Cancer | volume = 62 | issue = 8 | pages = 1058–1066 | date = 2010-11-05 | pmid = 21058193 | pmc = 4104190 | doi = 10.1080/01635581.2010.492089 }}</ref> It is a ], meaning it is related to ], and is found in small quantities naturally in the body. Its ], ], is also an acne drug. |
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The most common adverse effects are dry lips (]), dry and fragile skin (]), ]<ref name=":5">{{cite journal | vauthors = Moy A, McNamara NA, Lin MC | title = Effects of Isotretinoin on Meibomian Glands | language = en-US | journal = Optometry and Vision Science | volume = 92 | issue = 9 | pages = 925–930 | date = September 2015 | pmid = 26154692 | doi = 10.1097/OPX.0000000000000656 | url = https://escholarship.org/uc/item/41k4v4h1 }}</ref> and an ]. Uncommon and rare side effects include muscle aches and pains (]s), and headaches. Some of those side effects can persist long after the discontinuation of the use of the drug.<ref name=":5" /> Isotretinoin may cause ], therefore the patient's ] should be regularly tested.<ref>{{Cite web | vauthors = Erşan M |date=2017-09-05 |title=Sivilce ilacı karaciğerini mahvetti |trans-title=Acne drug destroyed her life |url=https://www.hurriyet.com.tr/gundem/sivilce-ilaci-karacigerini-mahvetti-40569183 |access-date=2024-06-20 |website=www.hurriyet.com.tr |language=tr |trans-quote=Prof. Dr. K. Yalçın Polat, President of the Department of General Surgery at the Memorial Ataşehir Hospital: Our patient's blood values were very high when she was hospitalized. It was not easy for us to decide to have a liver transplant. During our three-week treatment, her liver values continued to rise and she entered liver failure, which made us take this decision. In the liver biopsy, we saw necrosis (non-living tissue) in the liver. If we had waited a little longer, she would have fallen into a coma and we would have then lost the patient. The cause of her liver failure is the medication she takes for acne. Unfortunately, this drug is very widely used. Liver enzymes should be closely monitored while taking isotretinoin. Every kind of drug reaches the liver, and each of them has side effects as well as positive effects. Even if the liver tolerates these and cleans the toxins, it can still be affected as in the case of Mrs. Çilingir.}}</ref> It is known to cause ] due to in-utero exposure because of the molecule's close resemblance to ], a natural vitamin A derivative that controls normal embryonic development. It is associated with psychiatric side effects, most commonly depression but also, more rarely, psychosis and unusual behaviors. Other rare side effects include ] and premature ], which have been reported to be persistent. |
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<!-- Society and culture --> |
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Isotretinoin was patented in 1969 and approved for medical use in 1982.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=978-3-527-60749-5 |page=476 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA476 }}</ref> In 2021, it was the 264th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Isotretinoin - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Isotretinoin | access-date = 14 January 2024}}</ref> |
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== Medical uses == |
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Isotretinoin is used primarily for persistent cystic acne.<ref name="pmid19588674">{{cite journal | vauthors = Merritt B, Burkhart CN, Morrell DS | title = Use of isotretinoin for acne vulgaris | journal = Pediatric Annals | volume = 38 | issue = 6 | pages = 311–20 | date = June 2009 | pmid = 19588674 | doi = 10.3928/00904481-20090512-01 }}</ref><ref name="pmid20436884">{{cite journal | vauthors = Layton A | title = The use of isotretinoin in acne | journal = Dermato-Endocrinology | volume = 1 | issue = 3 | pages = 162–9 | date = May 2009 | pmid = 20436884 | pmc = 2835909 | doi = 10.4161/derm.1.3.9364 }}</ref><ref name=UKLabel2015/><ref name=USlabel2010/> Many dermatologists also support its use for treatment of lesser degrees of acne that prove resistant to other treatments, or that produce scarring or psychological distress.<ref name="pmid17276540">{{cite journal | vauthors = Strauss JS, Krowchuk DP, Leyden JJ, Lucky AW, Shalita AR, Siegfried EC, Thiboutot DM, Van Voorhees AS, Beutner KA, Sieck CK, Bhushan R | title = Guidelines of care for acne vulgaris management | journal = Journal of the American Academy of Dermatology | volume = 56 | issue = 4 | pages = 651–63 | date = April 2007 | pmid = 17276540 | doi = 10.1016/j.jaad.2006.08.048 }}</ref> Isotretinoin is not indicated for the treatment of prepubertal acne and is not recommended in children less than 12 years of age.<ref name=":0">{{cite web|date=August 2017|title=Isotretinoin (oral formulations): CMDH scientific conclusions – Scientific conclusions and grounds for the variation to the terms of the Marketing Authorisation(s)|url=https://www.ema.europa.eu/en/documents/psusa/isotretinoin-oral-formulations-cmdh-scientific-conclusions-grounds-variation-amendments-product/00010488/201611_en.pdf|access-date=17 May 2019|publisher=]}}</ref> |
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It is also somewhat effective for ] and some cases of severe ].<ref name="Micromedex">{{cite book | veditors = Klasco RK | title = Drugdex System | volume = 128 | location = Greenwood Village (CO) | publisher = Thomson Micromedex | date = 2006}} {{Page needed|date=May 2012}}</ref> It can also be used to help treat ], ] and is used in ] cases to relieve ]s. Isotretinoin has been used to treat the extremely rare condition ]. It is also used for the treatment of ] in Japan, but data for its efficacy is not conclusive and it has not been approved in other countries.<ref>{{cite journal | vauthors = Makimoto A, Fujisaki H, Matsumoto K, Takahashi Y, Cho Y, Morikawa Y, Yuza Y, Tajiri T, Iehara T | title = Retinoid Therapy for Neuroblastoma: Historical Overview, Regulatory Challenges, and Prospects | journal = Cancers | volume = 16 | issue = 3 | pages = 544 | date = January 2024 | pmid = 38339295 | pmc = 10854948 | doi = 10.3390/cancers16030544 | doi-access = free }}</ref> |
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Isotretinoin therapy has furthermore proven effective against ] in experimental use but is rarely used for this indication as there are more effective treatments. Isotretinoin may represent an efficacious and safe alternative systemic form of therapy for ] (RCA) of the cervix. In most countries, this therapy is currently unapproved and only used if other therapies fail.<ref name=Oral_isotretinoin_Therapy>{{cite journal | vauthors = Georgala S, Katoulis AC, Georgala C, Bozi E, Mortakis A | title = Oral isotretinoin in the treatment of recalcitrant condylomata acuminata of the cervix: a randomised placebo controlled trial | journal = Sexually Transmitted Infections | volume = 80 | issue = 3 | pages = 216–8 | date = June 2004 | pmid = 15170007 | pmc = 1744851 | doi = 10.1136/sti.2003.006841 }}</ref><ref name=Unapproved_Isotretinoin>{{cite journal | vauthors = Sehgal VN, Srivastava G, Sardana K | title = Isotretinoin--unapproved indications/uses and dosage: a physician's reference | journal = International Journal of Dermatology | volume = 45 | issue = 6 | pages = 772–7 | date = June 2006 | pmid = 16796650 | doi = 10.1111/j.1365-4632.2006.02830.x | s2cid = 10994239 }}</ref> |
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=== Prescribing restrictions === |
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Isotretinoin is a ]; there is about a 20–35% risk for congenital defects in infants exposed to the drug ''in utero'', and about 30–60% of children exposed to isotretinoin prenatally have been reported to show neurocognitive impairment.<ref name=Choi2013>{{cite journal | vauthors = Choi JS, Koren G, Nulman I | title = Pregnancy and isotretinoin therapy | journal = Canadian Medical Association Journal | volume = 185 | issue = 5 | pages = 411–3 | date = March 2013 | pmid = 23296582 | pmc = 3602257 | doi = 10.1503/cmaj.120729 }}</ref> Because of this risk, there are strict controls prescribing isotretinoin to women who have potential to become (or be) pregnant while taking isotretinoin and many are strongly advised to terminate their pregnancies because of the 20-60% risk.<ref name=Choi2013/> |
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In the United States, since March 2006, the dispensing of isotretinoin is run through the ], under the direction of the ].<ref>{{cite journal | vauthors = Thiboutot DM, Cockerell CJ | title=iPLEDGE: A Report from the Front Lines of Dermatologic Practice | journal=The Virtual Mentor | volume=8 | issue=8 | pages=524–528 | date=August 2006 | pmid=23234692 | doi=10.1001/virtualmentor.2006.8.8.pfor1-0608 | doi-access=free }}</ref><ref>{{cite news| vauthors=Darves B |title=Dermatologists Frustrated With Problematic iPledge Program|url=https://www.medscape.com/viewarticle/525664|work=Medscape|date=9 March 2006}}</ref> Prescribers, pharmacists, and all people to whom the drug is prescribed need to register on the site and log information into it. Women with child-bearing potential must commit to using two forms of effective contraception simultaneously for the duration of isotretinoin therapy and for a month immediately preceding and a month immediately following therapy. Additionally, they must have two negative ]s 30 days apart and have negative pregnancy tests before each prescription is written.<ref>{{cite web | url = https://www.ipledgeprogram.com/AboutiPLEDGE.aspx | title = iPledge (About iPledge) | access-date = 20 February 2011 | archive-date = 29 July 2017 | archive-url = https://web.archive.org/web/20170729005803/https://www.ipledgeprogram.com/AboutiPLEDGE.aspx | url-status = dead }}</ref><ref>{{cite web | url = https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm094305.htm | title=Isotretinoin (marketed as Accutane) Capsule Information|publisher=U.S. Food and Drug Administration (FDA)| date=3 November 2018}}</ref> |
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In most countries, isotretinoin can only be prescribed by dermatologists or specialist physicians; some countries also allow limited prescriptions by general practitioners and family doctors. In the United Kingdom<ref name="BNF47">{{cite book |author=Joint Formulary Committee |title=British National Formulary |title-link=British National Formulary |year=2004 |publisher=British Medical Association and Royal Pharmaceutical Society of Great Britain |isbn=978-0-85369-584-4 |edition=47th |location=London}}{{Page needed|date=May 2012}}</ref> and Australia,<ref>{{cite journal |date=19 June 2012 |title=Fresh call for GPs to prescribe Roaccutane |url=http://www.australiandoctor.com.au/news/latest-news/fresh-call-for-gps-to-prescribe-roaccutane |journal=AustralianDoctor |access-date=7 February 2014 |archive-date=12 April 2017 |archive-url=https://web.archive.org/web/20170412063909/https://www.australiandoctor.com.au/news/latest-news/fresh-call-for-gps-to-prescribe-roaccutane |url-status=dead }}</ref><ref>Specifically, doctors who are fellows of the Australasian College of Dermatologists (FACD); cf. Pharmaceutical Services Branch, ''Guide to poisons and therapeutic goods legislation for medical practitioners and dentists'', Sydney: NSW Department of Health; 2006.{{Page needed|date=October 2010}}</ref> isotretinoin may be prescribed only by or under the supervision of a consultant ]. Because severe cystic acne has the potential to cause permanent scarring over a short period, restrictions on its more immediate availability have proved contentious.<ref name="James_1996">{{cite journal |vauthors=James M |date=June 1996 |title=Isotretinoin for severe acne |journal=Lancet |volume=347 |issue=9017 |pages=1749–50 |doi=10.1016/S0140-6736(96)90814-4 |pmid=8656912 |s2cid=28756302}}</ref> In New Zealand, isotretinoin can be prescribed by any doctor but subsidized only when prescribed by a vocationally-registered general practitioner, dermatologist or nurse practitioner.<ref>{{Cite web |date=June 2013 |title=Acne, Isotretinoin, and Depression |url=http://www.medsafe.govt.nz/profs/puarticles/isotretdtb.htm |access-date=7 February 2014 |publisher=MEDSAFE (New Zealand Ministry of Health) |orig-year=June 2005}}</ref> |
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== Adverse effects == |
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Increasingly higher dosages will result in higher toxicity, resembling ]. Adverse effects include:<ref name=UKlabel>{{Cite web|url=https://www.medicines.org.uk/emc/medicine/15655|title=Isotretinoin 20mg capsules - - (eMC)|website=www.medicines.org.uk|access-date=27 December 2017|archive-date=28 December 2017|archive-url=https://web.archive.org/web/20171228054206/https://www.medicines.org.uk/emc/medicine/15655|url-status=dead}}</ref> |
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{| class="wikitable" |
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! colspan="5" |According to information leaflets<ref name="UKlabel" /> |
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!According to studies |
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Type of disorders |
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Very common (≥ 1/10) |
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Common (≥ 1/100, < 1/10) |
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Rare (≥ 1/{{Val|10000}},< 1/1000) |
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Very rare (≤ 1/{{Val|10000}}) |
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!Unknown Frequency |
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!Frequency |
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| '''Infections''' |
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* Gram-positive (mucocutaneous) bacterial infection |
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| '''Blood and ]''' |
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* ] |
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* Increased ] |
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* ] |
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* ] |
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* ] |
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* ] |
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| ''']''' |
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* Allergic skin reaction |
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* ] reactions |
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* Hypersensitivity |
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| ''']''' |
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* ] |
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* ] |
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| ''']''' |
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* ] |
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* Aggravated depression |
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* Aggressive tendencies |
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* ] |
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* Mood alterations |
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* Abnormal behaviour |
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* Psychotic disorder |
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* Suicidal ideation |
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* Suicide attempt |
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* ] |
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|Psychiatric: 25.15%<ref name=":4" /> |
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| ''']''' |
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* Headache |
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* ] |
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* ] |
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* ] |
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* ] |
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* Eye irritation |
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* Blurred vision |
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* ] |
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* ] |
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* Contact lens intolerance |
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* ] |
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* Decreased night vision |
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* ] |
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* ] |
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* ] |
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* Visual disturbances |
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* ] (i.e. ], allergic vasculitis) |
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| '''Respiratory, ]''' <br /> |
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'''and ]''' |
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* ] |
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* Nasal dryness |
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* ] |
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* ] (particularly in people with asthma) |
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* ] |
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* ] |
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* ] |
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* Dry throat |
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* ] |
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* Haemorrhagic diarrhoea |
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* ] |
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* ] |
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* ] |
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* Increased ] |
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* ] |
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| '''Skin and'''<br /> |
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''']''' |
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* ] |
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* ] |
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* ] |
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* Localised exfoliation |
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* ] |
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* Rash erythematous |
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* Skin fragility (with a risk of frictional trauma) |
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* Paronychia |
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* ] |
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* ] |
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* Aggravated acne (acne flare) |
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* ] (facial) |
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* ] |
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* Hair disorders |
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* ] |
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* ] |
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* ] |
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* ] |
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* ] |
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* ] |
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* Skin ] |
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* Increased sweating |
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* ] |
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* ] |
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* ]. |
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|100%<ref name=":4">{{cite journal | vauthors = Brzezinski P, Borowska K, Chiriac A, Smigielski J | title = Adverse effects of isotretinoin: A large, retrospective review | journal = Dermatologic Therapy | volume = 30 | issue = 4 | pages = e12483 | date = July 2017 | pmid = 28295859 | doi = 10.1111/dth.12483 | doi-access = free }}</ref> |
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| '''] and'''<br /> |
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''']''' |
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* ] |
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* ] |
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* Back pain |
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* ] |
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* ] (calcification of ligaments |
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and tendons) |
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* Premature epiphyseal fusion |
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* ] |
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* ] |
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* ] |
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* ] |
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| '''] and ]''' |
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* ] |
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* Dark or cola-coloured urine<ref name=":0" /> |
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|'''] and breast disorders''' |
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* Sexual dysfunction, including ] and ] |
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| '''General''' |
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* Increased formation of ] |
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* ] |
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| '''Investigation'''{{Clarify|reason=What does it mean for disorders to be listed under "investigation"?|date=January 2019}} |
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* Increased ] |
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* Decreased ] |
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* Increased blood cholesterol |
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* Increased blood glucose |
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* ] |
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* ] |
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* Increased ] |
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===Possible permanent effects=== |
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The effects of isotretinoin may be permanent. This has been proposed to be due to induction of apoptosis in ]s, ]s, ] cells, ] cells, ] cells, ] ascites cells, ], ] cells, ]s and others,<ref>{{cite journal | vauthors = Melnik BC | title = Isotretinoin and FoxO1: A scientific hypothesis | journal = Dermato-Endocrinology | volume = 3 | issue = 3 | pages = 141–165 | date = July 2011 | pmid = 22110774 | doi = 10.4161/derm.15331 | pmc = 3219165 }}</ref> that it changes ]<ref>{{Cite journal | vauthors = Becker E, Bengs S, Aluri S, Opitz L, Atrott K, Rost F, Leonardi I, Stanzel C, Raselli T, Kasper S, Ruiz PA |date= December 2017 |title=Large-Scale Integrative Analysis of Epigenetic Modifications Induced by Isotretinoin, Doxycycline and Metronidazole in Murine Colonic Intestinal Epithelial Cells |journal=Epigenomes |language=en |volume=1 |issue=3 |pages=24 |doi=10.3390/epigenomes1030024 |doi-access= free |issn=2075-4655}}</ref> and shortens ]s.<ref>{{cite journal | vauthors = Pendino F, Flexor M, Delhommeau F, Buet D, Lanotte M, Segal-Bendirdjian E | title = Retinoids down-regulate telomerase and telomere length in a pathway distinct from leukemia cell differentiation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 12 | pages = 6662–6667 | date = June 2001 | pmid = 11371621 | pmc = 34517 | doi = 10.1073/pnas.111464998 | doi-access = free | bibcode = 2001PNAS...98.6662P }}</ref> |
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Isotretinoin may stop ] growth in young people who are still growing.<ref name="USlabel2010">{{Cite report |orig-year= January 2010 |title= US Label |url= http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018662s060lbl.pdf |publisher= FDA |date= 22 October 2010 |access-date= 1 June 2017 }} See for updates</ref> Premature ] closure can occur in people receiving recommended doses<ref>{{Cite web|url=https://www.medicines.org.uk/emc/medicine/15655|title=Isotretinoin 20mg capsules - - (eMC)|website=www.medicines.org.uk|access-date=10 January 2018|archive-date=28 December 2017|archive-url=https://web.archive.org/web/20171228054206/https://www.medicines.org.uk/emc/medicine/15655|url-status=dead}}</ref> of Accutane.<ref>{{cite journal | vauthors = David M, Hodak E, Lowe NJ | title = Adverse effects of retinoids | journal = Medical Toxicology and Adverse Drug Experience | volume = 3 | issue = 4 | pages = 273–88 | year = 1988 | pmid = 3054426 | doi = 10.1007/bf03259940 | s2cid = 12432684 }}</ref><ref>{{cite journal | vauthors = DiGiovanna JJ | title = Isotretinoin effects on bone | journal = Journal of the American Academy of Dermatology | volume = 45 | issue = 5 | pages = S176-82 | date = November 2001 | pmid = 11606950 | doi = 10.1067/mjd.2001.113721 }}</ref><ref>{{cite journal | vauthors = Ellis CN, Madison KC, Pennes DR, Martel W, Voorhees JJ | title = Isotretinoin therapy is associated with early skeletal radiographic changes | journal = Journal of the American Academy of Dermatology | volume = 10 | issue = 6 | pages = 1024–9 | year = 1984 | pmid = 6588057 | doi = 10.1016/S0190-9622(84)80329-1 }}</ref><ref name=":6">{{Cite web |date=October 2014 |title=Isotretinoin risks in acne treatment: Page 3 of 4 |url=https://www.contemporarypediatrics.com/acne/isotretinoin-risks-acne-treatment/page/0/2 |url-status=dead |archive-url=https://web.archive.org/web/20190609150806/https://www.contemporarypediatrics.com/acne/isotretinoin-risks-acne-treatment/page/0/2 |archive-date=9 June 2019 |access-date=9 June 2019}}</ref> |
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Isotretinoin is known to cause ] dysfunction which causes persistent ] (dry eye).<ref name=Moy2015rev>{{cite journal | vauthors = Moy A, McNamara NA, Lin MC | title = Effects of Isotretinoin on Meibomian Glands | journal = Optometry and Vision Science | volume = 92 | issue = 9 | pages = 925–30 | date = September 2015 | pmid = 26154692 | doi = 10.1097/OPX.0000000000000656 | s2cid = 205905994 | url = http://www.escholarship.org/uc/item/41k4v4h1 }}</ref> Problems with the meibomian and salivary glands are likely due to the ] ] of the cells of the ]s.<ref name="Lambert_1989" /> Decreased ] has been reported to persist in some people after discontinuation of isotretinoin therapy,<ref name="autogenerated299">{{cite journal | vauthors = Fraunfelder FT, Fraunfelder FW, Edwards R | title = Ocular side effects possibly associated with isotretinoin usage | journal = American Journal of Ophthalmology | volume = 132 | issue = 3 | pages = 299–305 | date = September 2001 | pmid = 11530040 | doi = 10.1016/S0002-9394(01)01024-8 | s2cid = 37897437 }}</ref><ref name="pmid34379039">{{cite journal |vauthors=Fallah H, Rademaker M |title=Isotretinoin for acne vulgaris - an update on adverse effects and laboratory monitoring |journal=The Journal of Dermatological Treatment |volume=33 |issue=5 |pages=2414–2424 |date=August 2022 |pmid=34379039 |doi=10.1080/09546634.2021.1967269 |quote=In summary, night vision impairment may occur in patients being treated with isotretinoin. Subclinical impairments in electrophysiological examination findings in the absence of any patient-reported changes in night vision may not be infrequent. The decline in night vision appears to be in most cases reversible upon cessation of isotretinoin, although subclinical abnormalities in electrophysiological tests may last longer than initially thought. Isotretinoin is thought to cause night vision impairment by inhibiting ocular retinol dehydrogenases, leading to a reduction in the formation of the visual chromophore 11-cis-retinal.}}</ref> although most cases of decreased night vision appear to resolve after discontinuing the medication.<ref name="pmid34379039"/> |
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=== Sexual === |
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Isotretinoin is also associated with permanent sexual side effects, namely ] and reduced ].<ref>{{cite journal | vauthors = Healy D, Bahrick A, Bak M, Barbato A, Calabrò RS, Chubak BM, Cosci F, Csoka AB, D'Avanzo B, Diviccaro S, Giatti S, Goldstein I, Graf H, Hellstrom WJ, Irwig MS, Jannini EA, Janssen PK, Khera M, Kumar MT, Le Noury J, Lew-Starowicz M, Linden DE, Lüning C, Mangin D, Melcangi RC, Rodríguez OW, Panicker JN, Patacchini A, Pearlman AM, Pukall CF, Raj S, Reisman Y, Rubin RS, Schreiber R, Shipko S, Vašečková B, Waraich A | title = Diagnostic criteria for enduring sexual dysfunction after treatment with antidepressants, finasteride and isotretinoin | journal = The International Journal of Risk & Safety in Medicine | volume = 33 | issue = 1 | pages = 65–76 | date = 2022-02-22 | pmid = 34719438 | pmc = 8925105 | doi = 10.3233/JRS-210023 }}</ref> In October 2017, the UK ] issued a Drug Safety Update to physicians in response to reports of these problems.<ref>{{cite web|date=3 October 2017|title=Drug Safety Update – Latest advice for medicines users – October 2017|url=https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/655127/DSU-Oct-pdf.pdf|access-date=17 May 2019|publisher=]}}</ref> This was in response to an EU review, published in August 2017, which states that a plausible physiological explanation of these side effects "may be a reduction in plasma testosterone".<ref name=":0" /> The review also stated that "the product information should be updated to include ‘sexual dysfunction including erectile dysfunction and decreased libido’ as an undesirable effect with an unknown frequency".<ref>{{cite web|date=1 September 2017|title=Pharmacovigilance Risk Assessment Committee (PRAC) – Minutes for the meeting on 3–6 July 2017|url=https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-3-6-july-2017_en.pdf|access-date=17 May 2019|publisher=European Medicines Agency|page=44}}</ref> There have also been reports of ] disorders, such as ]. 27 cases of sexual dysfunction report either negative ] or positive dechallenge.{{clarify|date=May 2019}}<ref name=":0" /> |
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=== Skin === |
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The most common side effects are mucocutaneous: dry lips, skin, and nose. Other common mucocutaneous side effects are inflammation and chapping of the lips (]), redness of the skin (]), rashes, peeling, eczema (]), itching (]) and nose bleeds (]).<ref name=Brelsford2008rev>{{cite journal | vauthors = Brelsford M, Beute TC | title = Preventing and managing the side effects of isotretinoin | journal = Seminars in Cutaneous Medicine and Surgery | volume = 27 | issue = 3 | pages = 197–206 | date = September 2008 | pmid = 18786498 | doi = 10.1016/j.sder.2008.07.002 | doi-broken-date = 9 December 2024 | url = https://zenodo.org/record/1259359 }}</ref> Absence of dryness of the lips is considered an indication of non-compliance with treatment (not taking the drug as advised), as it occurs in almost all people who take it.<ref name=Brelsford2008rev/> |
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Regular use of lip balm and moisturizer is recommended throughout treatment to reduce these problems. The dose may need to be decreased to reduce the severity of these side effects.<ref name="pmid16703787">{{cite journal | vauthors = Scheinfeld N, Bangalore S | title = Facial edema induced by isotretinoin use: a case and a review of the side effects of isotretinoin | journal = Journal of Drugs in Dermatology | volume = 5 | issue = 5 | pages = 467–8 | date = May 2006 | pmid = 16703787 }}</ref> The skin becomes more fragile—especially to frictional forces—and may not heal as quickly as normal. Wound healing is delayed. For this reason, elective surgery, waxing of hair, tattooing, tattoo removal, piercings, dermabrasion, exfoliation, etc., are not recommended. Treatment of acne scars is generally deferred until 12 months after completion of a course of isotretinoin. |
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=== Teratogenicity === |
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{{anchor|Teratogenicity (Birth defects)|Teratogenicity (birth defects)}} <!-- This section is linked from ] --> |
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Isotretinoin is a ] highly likely to cause birth defects if taken by women during pregnancy or even a short time before conception. A few of the more common birth defects this drug can cause are hearing and visual impairment, missing or malformed earlobes, facial dysmorphism, and abnormalities in brain function. Isotretinoin is classified as ] ] X and ] Category X, and use is contraindicated in pregnancy.<ref name="Micromedex" /> In the EU, isotretinoin (oral) is contraindicated in pregnancy and must not be taken by women able to have children unless the conditions of a pregnancy prevention program are met.<ref name=":2" /> |
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The manufacturer recommends pregnancy be ruled out two weeks before commencement of isotretinoin, and women should use two simultaneous forms of effective contraception at least one month before commencement, during, and for at least one month following isotretinoin therapy.<ref name="RoaccutanePI">Roche Products Pty Ltd. Roaccutane (Australian Approved Product Information). Dee Why (NSW): Roche; 2005.{{Page needed|date=October 2010}}</ref> |
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In the US, around 2000 women became pregnant while taking the drug between 1982 and 2000, with most pregnancies ending in ] or ]. About 160 babies with birth defects were born. After the FDA put the more strict iPLEDGE program in place for the companies marketing the drug in the US, in 2011, 155 pregnancies occurred (0.12%) among 129,544 women of childbearing potential taking isotretinoin.<ref>{{cite journal | vauthors = Leyden JJ, Del Rosso JQ, Baum EW | title = The use of isotretinoin in the treatment of acne vulgaris: clinical considerations and future directions | journal = The Journal of Clinical and Aesthetic Dermatology | volume = 7 | issue = 2 Suppl | pages = S3–S21 | date = February 2014 | pmid = 24688620 | pmc = 3970835 }}</ref> |
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People taking isotretinoin are not permitted to donate blood during and for at least one month after discontinuation of therapy due to its teratogenicity.<ref>BNF, edition 57{{Page needed|date=October 2010}}</ref> |
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===Psychological effects=== |
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Rare psychological side effects may include depression, worsening of pre-existing depression, aggressive tendencies, irritable mood, and anxiety. Very rare effects include abnormal behaviour, ], suicidal ideation, suicide attempts, and ].<ref name="UKLabel2015" /><ref name="Bremner2012rev" /><ref name="Kontaxakis2009rev">{{cite journal | vauthors = Kontaxakis VP, Skourides D, Ferentinos P, Havaki-Kontaxaki BJ, Papadimitriou GN | title = Isotretinoin and psychopathology: a review | journal = Annals of General Psychiatry | volume = 8 | pages = 2 | date = January 2009 | pmid = 19154613 | pmc = 2637283 | doi = 10.1186/1744-859X-8-2 |doi-access=free}}</ref><ref name="Borovaya2013rev">{{cite journal | vauthors = Borovaya A, Olisova O, Ruzicka T, Sárdy M | title = Does isotretinoin therapy of acne cure or cause depression? | journal = International Journal of Dermatology | volume = 52 | issue = 9 | pages = 1040–52 | date = September 2013 | pmid = 23962262 | doi = 10.1111/ijd.12169 | s2cid = 26521263 }}</ref> In a total of 5577 ] reported to the UK's ] up to 31 March 2017, the plurality (1207, or 22%) concerned psychiatric effects.<ref name="MHRAreport">{{Cite web|url=https://info.mhra.gov.uk/drug-analysis-profiles/dap.html?drug=./UK_EXTERNAL/NONCOMBINED/UK_NON_000285965613.zip&agency=MHRA|title=Interactive Drug Analysis Profile - Isotretinoin|date=31 March 2017|website=mhra.gov.uk|publisher=Medicines & Healthcare Products Regulatory Agency}}</ref> There were 85 reports of suicidal ideation, 56 of suicide and 43 of suicide attempts.<ref name="MHRAreport" /> |
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Isotretinoin decreases the brain metabolism in the orbitofrontal cortex by an average of 21%, a brain area known to mediate symptoms of depression.<ref>{{cite journal | vauthors = Bremner JD, Fani N, Ashraf A, Votaw JR, Brummer ME, Cummins T, Vaccarino V, Goodman MM, Reed L, Siddiq S, Nemeroff CB | title = Functional brain imaging alterations in acne patients treated with isotretinoin | journal = The American Journal of Psychiatry | volume = 162 | issue = 5 | pages = 983–991 | date = May 2005 | pmid = 15863802 | doi = 10.1176/appi.ajp.162.5.983 }}</ref> |
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The association between isotretinoin use and psychopathology has been controversial. Beginning in 1983, isolated case reports emerged suggesting mood change, particularly depression, occurring during or soon after isotretinoin use.<ref name="bjd2010">{{cite journal | vauthors = Goodfield MJ, Cox NH, Bowser A, McMillan JC, Millard LG, Simpson NB, Ormerod AD | title = Advice on the safe introduction and continued use of isotretinoin in acne in the U.K. 2010 | journal = The British Journal of Dermatology | volume = 162 | issue = 6 | pages = 1172–9 | date = June 2010 | pmid = 21250961 | doi = 10.1111/j.1365-2133.2010.09836.x |doi-access=| s2cid = 7714558 }}</ref> Several studies have been conducted since then of the drug's effect on depression, psychosis, suicidal thoughts and other psychological effects.<ref name="bjd2010" /> |
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==== Depression and suicidality ==== |
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Isotretinoin is the only non-psychiatric drug on the ]'s top 10 list of drugs associated with depression<ref name="Kontaxakis2009rev" /><ref name=":1">{{cite journal | vauthors = Ludot M, Mouchabac S, Ferreri F | title = Inter-relationships between isotretinoin treatment and psychiatric disorders: Depression, bipolar disorder, anxiety, psychosis, and suicide risks | journal = World Journal of Psychiatry | volume = 5 | issue = 2 | pages = 222–7 | date = June 2015 | pmid = 26110123 | pmc = 4473493 | doi = 10.5498/wjp.v5.i2.222 |doi-access=free}}</ref> and is also within the top 10 for suicide attempts.<ref>{{cite journal | vauthors = Wysowski DK, Pitts M, Beitz J | title = An analysis of reports of depression and suicide in patients treated with isotretinoin | journal = Journal of the American Academy of Dermatology | volume = 45 | issue = 4 | pages = 515–9 | date = October 2001 | pmid = 11568740 | doi = 10.1067/mjd.2001.117730 | url = https://zenodo.org/record/1236038 }}</ref> A ] for suicide, depression, and psychosis has been present on isotretinoin's packaging in the United States since 2005.<ref name=":1" /> In March 2018, ] issued a warning on a possible risk of neuropsychiatric disorders (such as depression, anxiety, and mood changes) following the use of oral retinoids, including isotretinoin, though the limitations of the available data did not allow them to establish whether this risk was due to the use of retinoids.<ref name=":2">{{Cite web|url=https://www.ema.europa.eu/en/medicines/human/referrals/retinoid-containing-medicinal-products|title=Updated measures for pregnancy prevention during retinoid use|date=21 June 2018|website=European Medicines Agency}}</ref> |
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A Swedish retrospective cohort study with 5756 patients showed a significantly increased risk of attempted suicides from 6 months after the treatment to around 2 years after the treatment.<ref>{{cite journal | vauthors = Sundström A, Alfredsson L, Sjölin-Forsberg G, Gerdén B, Bergman U, Jokinen J | title = Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study | journal = BMJ | volume = 341 | issue = nov11 1 | pages = c5812 | date = November 2010 | pmid = 21071484 | pmc = 2978759 | doi = 10.1136/bmj.c5812 }}</ref> |
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In 2012, a systematic review covering all articles in the literature related to isotretinoin, depression, and suicide, as well as articles related to class effect, dose-response, and biological plausibility found that the literature reviewed was consistent with an association of isotretinoin administration and depression and with suicide in a subgroup of vulnerable individuals.<ref name="Bremner2012rev">{{cite journal | vauthors = Bremner JD, Shearer KD, McCaffery PJ | title = Retinoic acid and affective disorders: the evidence for an association | journal = The Journal of Clinical Psychiatry | volume = 73 | issue = 1 | pages = 37–50 | date = January 2012 | pmid = 21903028 | pmc = 3276716 | doi = 10.4088/JCP.10r05993 | type = Systematic Review }}</ref> Following this systematic review, in a 2014 review a group of Australian dermatologists and psychiatrists collaborated on a set of recommendations for safe prescribing of isotretinoin.<ref name="Rowe2014">{{cite journal | vauthors = Rowe C, Spelman L, Oziemski M, Ryan A, Manoharan S, Wilson P, Daubney M, Scott J | title = Isotretinoin and mental health in adolescents: Australian consensus | journal = The Australasian Journal of Dermatology | volume = 55 | issue = 2 | pages = 162–7 | date = May 2014 | pmid = 24283385 | doi = 10.1111/ajd.12117 | s2cid = 29178483 | type = Review }}</ref> However, whether isotretinoin use is causally associated with mental illness remains controversial.<ref name="Rowe2014" /> |
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Evidence for depression being causally associated with isotretinoin use includes 41 reports of positive ] with isotretinoin, involving administering isotretinoin, withdrawing the drug, and then re-administering it.<ref name="Bremner2012rev" /> The majority of these cases had no psychiatric history.<ref name="Bremner2012rev" /> There is also a temporal relationship between the development of depression and initiation of isotretinoin treatment, with most cases developing after 1–2 months of treatment.<ref name="Bremner2012rev" /> Further, higher doses of isotretinoin increase the risk of developing depression, with 25% of people showing depression on a dose of 3 mg/kg/day as compared with 3–4% at normal doses.<ref name="Bremner2012rev" /> Studies have uncovered ] which may credibly explain the affective changes induced by isotretinoin.{{CN|date=June 2023}} |
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==== Psychosis ==== |
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Isotretinoin has also been linked to psychosis.<ref name=UKlabel/> Many of the side effects of isotretinoin mimic hypervitaminosis A, which has been associated with psychotic symptoms.<ref name="Bremner2012rev" /> The dopamine hypothesis of schizophrenia and psychosis suggests that an increase in dopaminergic stimulation or sensitivity in the limbic system causes psychotic symptoms.<ref>{{cite journal | vauthors = Palha JA, Goodman AB | title = Thyroid hormones and retinoids: a possible link between genes and environment in schizophrenia | journal = Brain Research Reviews | volume = 51 | issue = 1 | pages = 61–71 | date = June 2006 | pmid = 16325258 | doi = 10.1016/j.brainresrev.2005.10.001 | hdl = 1822/3943 | s2cid = 30773986 | url = http://repositorium.sdum.uminho.pt/bitstream/1822/3943/1/Palha%20and%20Goodman%202005%20BRR.pdf | hdl-access = free }}</ref> |
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It has been suggested that dysregulation of retinoid receptors by retinoids such as isotretinoin may cause schizophrenia.<ref name=":3">{{cite journal | vauthors = Goodman AB | title = Retinoid dysregulation as a cause of schizophrenia | journal = The American Journal of Psychiatry | volume = 151 | issue = 3 | pages = 452–3 | date = March 1994 | pmid = 8109664 | doi=10.1176/ajp.151.3.452b}}</ref><ref>{{cite journal | vauthors = Goodman AB | title = Congenital anomalies in relatives of schizophrenic probands may indicate a retinoid pathology | journal = Schizophrenia Research | volume = 19 | issue = 2–3 | pages = 163–70 | date = May 1996 | pmid = 8789914 | doi=10.1016/0920-9964(96)88523-9| s2cid = 12089905 }}</ref> The evidence for this is threefold: transcriptional activation of the ] – in addition to serotonin and ]s – is regulated by ];<ref name=":3" /> schizophrenia and the retinoid ] have been linked to the same ];<ref name=":3" /> and retinoid dysfunction causes congenital anomalies identical to those observed in people with schizophrenia.<ref name=":3" /> Further, the expression of dopamine receptors has indeed been shown to be regulated by retinoic acid.<ref>{{cite journal | vauthors = Goodman AB | title = Microarray results suggest altered transport and lowered synthesis of retinoic acid in schizophrenia | journal = Molecular Psychiatry | volume = 10 | issue = 7 | pages = 620–1 | date = July 2005 | pmid = 15838536 | doi = 10.1038/sj.mp.4001668 |doi-access=free}}</ref><ref>{{cite journal | vauthors = Samad TA, Krezel W, Chambon P, Borrelli E | title = Regulation of dopaminergic pathways by retinoids: activation of the D2 receptor promoter by members of the retinoic acid receptor-retinoid X receptor family | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 26 | pages = 14349–54 | date = December 1997 | pmid = 9405615 | doi=10.1073/pnas.94.26.14349 |doi-access=free | pmc=24972| bibcode = 1997PNAS...9414349S }}</ref> |
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=== Musculoskeletal === |
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Isotretinoin has a number of ] effects. ] (muscular pain) and ] (joint pain) are common side effects.<ref name="Brelsford2008rev"/> ]s, such as high dose etretinate, are well known to cause bone changes, the most common type of which is ] (excessive bone growth), especially in growing children and adolescents.<ref name="Brelsford2008rev"/> While excessive bone growth has been raised as a possible side effect of isotretinoin, a 2006 review found little evidence for this.<ref>{{cite journal | vauthors = Halverstam CP, Zeichner J, Lebwohl M | title = Lack of significant skeletal changes after long-term, low-dose retinoid therapy: case report and review of the literature | journal = ] | volume = 10 | issue = 6 | pages = 291–9 | date = 2006 | pmid = 17241599 | doi = 10.2310/7750.2006.00065 | s2cid = 36785828 }}</ref> Other problems include premature ] and ] of tendons and ligaments.<ref name="Brelsford2008rev"/> The bones of the spine and feet are most commonly affected. Risk factors for skeletal effects include older age, greater dosage, and longer course of treatment. Most bone changes cause no symptoms and may only be noticed using ].<ref name="Brelsford2008rev"/> |
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=== Gastrointestinal === |
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Isotretinoin may cause non-specific gastrointestinal symptoms including nausea, diarrhea, and abdominal pain.<ref name=Brelsford2008rev/> The drug is associated with ] (IBD)—], but not Crohn's disease.<ref>{{cite journal | vauthors = Crockett SD, Porter CQ, Martin CF, Sandler RS, Kappelman MD | title = Isotretinoin use and the risk of inflammatory bowel disease: a case-control study | journal = The American Journal of Gastroenterology | volume = 105 | issue = 9 | pages = 1986–93 | date = September 2010 | pmid = 20354506 | pmc = 3073620 | doi = 10.1038/ajg.2010.124 }}</ref> There are also reports of people developing ] (IBS) and worsening of existing IBS.<ref>{{cite journal | vauthors = Lowenstein EB, Lowenstein EJ | title = Isotretinoin systemic therapy and the shadow cast upon dermatology's downtrodden hero | journal = Clinics in Dermatology | volume = 29 | issue = 6 | pages = 652–61 | pmid = 22014987 | doi = 10.1016/j.clindermatol.2011.08.026 |year=2011}}</ref> |
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=== Eyes === |
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Isotretinoin and other retinoids are well known to affect the eyes. ] are very common during treatment and is caused by isotretinoin's apoptotic effect on the ]s. Some people develop contact lens intolerance as a result.<ref name=Brelsford2008rev/> In some people, these changes are long-lasting or irreversible and represent ] (MGD).<ref name=Moy2015rev/> Other common effects on the eyes include inflammation of the eyelid (]), red eye caused by ] and irritation of the eye. More rare ocular side effects include blurred vision, decreased night vision (which may be permanent), ], development of corneal opacities, inflammation of the cornea (]), swelling of the optic disk (], associated with ]), ] and other visual disturbances.<ref name=UKLabel2015>{{cite web|title=Roaccutane 20mg Soft Capsules - Summary of Product Characteristics|url=https://www.medicines.org.uk/emc/medicine/21511|publisher=UK Electronic Medicines Compendium|date=1 July 2015}}</ref> |
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==Pharmacology== |
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=== Mechanism of action === |
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Isotretinoin's exact ] is unknown, but several studies have shown that isotretinoin induces ] (programmatic cell death) in various cells in the body. Cell death may be instigated in the ]s,<ref name="Lambert_1989">{{cite journal | vauthors = Lambert RW, Smith RE | title = Effects of 13-cis-retinoic acid on the hamster meibomian gland | journal = The Journal of Investigative Dermatology | volume = 92 | issue = 3 | pages = 321–5 | date = March 1989 | pmid = 2918239 | doi = 10.1111/1523-1747.ep12277122 |doi-access=free}}</ref><ref name="Kremer1994">{{cite journal | vauthors = Kremer I, Gaton DD, David M, Gaton E, Shapiro A | title = Toxic effects of systemic retinoids on meibomian glands | journal = Ophthalmic Research | volume = 26 | issue = 2 | pages = 124–8 | year = 1994 | pmid = 8196934 | doi = 10.1159/000267402 }}</ref> ] cells,<ref name="Griffin_2010">{{cite journal | vauthors = Griffin JN, Pinali D, Olds K, Lu N, Appleby L, Doan L, Lane MA | title = 13-Cis-retinoic acid decreases hypothalamic cell number in vitro | journal = Neuroscience Research | volume = 68 | issue = 3 | pages = 185–90 | date = November 2010 | pmid = 20708044 | doi = 10.1016/j.neures.2010.08.003 | s2cid = 207152111 }}</ref> ] cells<ref name="Crandall2004">{{cite journal | vauthors = Crandall J, Sakai Y, Zhang J, Koul O, Mineur Y, Crusio WE, McCaffery P |author-link6 = Wim Crusio | title = 13-cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 14 | pages = 5111–6 | date = April 2004 | pmid = 15051884 | pmc = 387382 | doi = 10.1073/pnas.0306336101 |doi-access=free | bibcode = 2004PNAS..101.5111C | jstor = 3371827 }}</ref><ref name="Sakai_2004">{{cite journal | vauthors = Sakai Y, Crandall JE, Brodsky J, McCaffery P | title = 13-cis Retinoic acid (accutane) suppresses hippocampal cell survival in mice | journal = Annals of the New York Academy of Sciences | volume = 1021 | issue = 1| pages = 436–40 | date = June 2004 | pmid = 15251924 | doi = 10.1196/annals.1308.059 | bibcode = 2004NYASA1021..436S | s2cid = 9588555 }}</ref> and—important for treatment of acne—in ] cells.<ref name="Nelson2011">{{cite journal | vauthors = Nelson AM, Cong Z, Gilliland KL, Thiboutot DM | title = TRAIL contributes to the apoptotic effect of 13-cis retinoic acid in human sebaceous gland cells | journal = The British Journal of Dermatology | volume = 165 | issue = 3 | pages = 526–33 | date = September 2011 | pmid = 21564055 | pmc = 3166444 | doi = 10.1111/j.1365-2133.2011.10392.x}}</ref><ref name="Nelson_2006">{{cite journal | vauthors = Nelson AM, Gilliland KL, Cong Z, Thiboutot DM | title = 13-cis Retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes | journal = The Journal of Investigative Dermatology | volume = 126 | issue = 10 | pages = 2178–89 | date = October 2006 | pmid = 16575387 | doi = 10.1038/sj.jid.5700289 |doi-access=free}}</ref> Isotretinoin has a low affinity for ]s (RAR) and ]s (RXR), but may be converted intracellularly to metabolites that act as ]s of RAR and RXR ]s.<ref name="pmid20436884" /> |
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One study suggests the drug amplifies production of ] (NGAL) in the skin, which has been shown to reduce ] production by inducing apoptosis in sebaceous gland cells, while exhibiting an antimicrobial effect on '']''.<ref>{{cite journal | doi = 10.1016/S0037-6337(09)70553-4 |title=Isotretinoin's Mechanism of Action Explored |year=2009 |journal=Skin & Allergy News |volume=40 |issue=11 |pages=32 | vauthors = Wachter K }}</ref><ref>{{cite web | url = http://www.medconnect.com.au/tabid/84/ct1/c333004/Isotretinoin-s-Mechanism-of-Action-Elucidated/Default.aspx | title = Isotretinoin's Mechanism of Action Elucidated | archive-url = https://web.archive.org/web/20100404060010/http://www.medconnect.com.au/tabid/84/ct1/c333004/Isotretinoin-s-Mechanism-of-Action-Elucidated/Default.aspx | archive-date = 4 April 2010 | work = Medconnect | publisher = Elsevier Global Medical News | date = 28 August 2009 | access-date = 13 November 2010 }}</ref><ref name="pmid18317594">{{cite journal | vauthors = Nelson AM, Zhao W, Gilliland KL, Zaenglein AL, Liu W, Thiboutot DM | title = Neutrophil gelatinase-associated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human sebaceous gland cells | journal = The Journal of Clinical Investigation | volume = 118 | issue = 4 | pages = 1468–78 | date = April 2008 | pmid = 18317594 | pmc = 2262030 | doi = 10.1172/JCI33869 }}</ref> The drug decreases the size and sebum output of the sebaceous glands.<ref name="Peck">{{cite journal | vauthors = Peck GL, Olsen TG, Yoder FW, Strauss JS, Downing DT, Pandya M, Butkus D, Arnaud-Battandier J | title = Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid | journal = The New England Journal of Medicine | volume = 300 | issue = 7 | pages = 329–33 | date = February 1979 | pmid = 153472 | doi = 10.1056/NEJM197902153000701 }}</ref> Isotretinoin is the only available acne drug that affects all four major pathogenic processes in acne, which distinguishes it from alternative treatments (such as antibiotics) and accounts for its efficacy in severe, nodulocystic cases.<ref>{{Cite journal|year=2001|journal= Journal of the European Academy of Dermatology and Venereology|volume=15|pages=43–9|author=Shalita A|doi=10.1046/j.0926-9959.2001.00012.x|pmid=11843233|title=The integral role of topical and oral retinoids in the early treatment of acne|s2cid= 22954658}}</ref> The effect of isotretinoin on sebum production can be temporary,<ref name=USlabel2010/> or remission of the disease can be "complete and prolonged."<ref name="Peck"/><ref name="Farrell">{{MEDRS|date=August 2013}}{{cite journal | vauthors = Farrell LN, Strauss JS, Stranieri AM | title = The treatment of severe cystic acne with 13-cis-retinoic acid. Evaluation of sebum production and the clinical response in a multiple-dose trial | journal = Journal of the American Academy of Dermatology | volume = 3 | issue = 6 | pages = 602–11 | date = December 1980 | pmid = 6451637 | doi = 10.1016/S0190-9622(80)80074-0 }}</ref><ref name="Jones">{{MEDRS|date=August 2013}}{{cite journal | vauthors = Jones H, Blanc D, Cunliffe WJ | title = 13-cis retinoic acid and acne | journal = Lancet | volume = 2 | issue = 8203 | pages = 1048–9 | date = November 1980 | pmid = 6107678 | doi = 10.1016/S0140-6736(80)92273-4 | s2cid = 40877032 }}</ref> |
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Isotretinoin has been speculated to down-regulate the enzyme ] and ], inhibiting "] and ]."<ref name="Pendino">{{cite journal | vauthors = Pendino F, Flexor M, Delhommeau F, Buet D, Lanotte M, Segal-Bendirdjian E | title = Retinoids down-regulate telomerase and telomere length in a pathway distinct from leukemia cell differentiation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 12 | pages = 6662–7 | date = June 2001 | pmid = 11371621 | pmc = 34517 | doi = 10.1073/pnas.111464998 | bibcode = 2001PNAS...98.6662P | jstor = 3055868 | doi-access = free }}</ref> In a 2007 study, isotretinoin was proven to inhibit the action of the metalloprotease ] (]) in ] without any influence in the action of ] and ] (the tissue inhibitors of metalloproteases).<ref>{{cite book | vauthors = Fahandidis PE |year=2007 |script-title=el:Η επίδραση της ισοτρετινοϊνης και των αναστολέων της 5α-αναγωγάσης στις μεταλλοπρωτεάσες του συνδετικού ιστού σε ασθενείς με ακμή |trans-title=The influence of isotretinoin and 5-a reductase inhibitors in metaloproteases of connective tissue in patients with ance |language=el |url=http://invenio.lib.auth.gr/record/103970 |publisher=]}}</ref>{{Unreliable medical source|date=April 2012}} It is already known that metalloproteases play an important role in the ] of acne.<ref name="pmid12102663">{{cite journal | vauthors = Toyoda M, Nakamura M, Makino T, Kagoura M, Morohashi M | title = Sebaceous glands in acne patients express high levels of neutral endopeptidase | journal = Experimental Dermatology | volume = 11 | issue = 3 | pages = 241–7 | date = June 2002 | pmid = 12102663 | doi = 10.1034/j.1600-0625.2002.110307.x | s2cid = 23468315 }}</ref> |
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==== CNS activities ==== |
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A possible biological basis for the case reports of depression involves decreased metabolism in the ] (OFC) of the ].<ref name=Bremner2012rev/> It has also been found that decreased OFC metabolism was correlated with headaches.<ref name="Bremner2012rev" /> People reporting headache as a side effect often report comorbid neuropsychiatric symptoms, especially depression; a statistically significant relationship between headache and depression has been established.<ref>{{cite journal | vauthors = Wysowski DK, Swartz L | title = Relationship between headache and depression in users of isotretinoin | language = en | journal = Archives of Dermatology | volume = 141 | issue = 5 | pages = 640–1 | date = May 2005 | pmid = 15897395 | doi = 10.1001/archderm.141.5.640 }}</ref> It is suggested that people sensitive to isotretinoin-induced CNS effects may also be susceptible to other psychiatric side effects such as depression.<ref name="Bremner2012rev" /> |
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Studies in mice and rats have found that retinoids, including isotretinoin, bind to ] in the central nervous system.<ref name=Kontaxakis2009rev/><ref>{{cite journal | vauthors = Magin P, Pond D, Smith W | title = Isotretinoin, depression and suicide: a review of the evidence | language = en | journal = The British Journal of General Practice | volume = 55 | issue = 511 | pages = 134–8 | date = February 2005 | pmid = 15720936 | pmc = 1463189 | url = http://bjgp.org/content/55/511/134 }}</ref><ref>{{cite journal | vauthors = Ng CH, Schweitzer I | title = The association between depression and isotretinoin use in acne | language = en | journal = The Australian and New Zealand Journal of Psychiatry | volume = 37 | issue = 1 | pages = 78–84 | date = February 2003 | pmid = 12534661 | doi = 10.1046/j.1440-1614.2003.01111.x| s2cid = 8475675 }}</ref> Isotretinoin may affect dopaminergic ] by disrupting the structure of dopamine receptors and decreasing dopaminergic activity.<ref name=Borovaya2013rev /> The dopaminergic system is implicated in numerous psychological disorders, including depression. Isotretinoin is also thought to affect the ] system – it increases expression of ] in the pre-synaptic neuron, which inhibit serotonin secretion.<ref name=Borovaya2013rev/> Isotretinoin also, directly and indirectly, increases the translation of the ] (SERT), leading to increased ] and consequently reduced synaptic availability of serotonin.<ref name=Borovaya2013rev/> |
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Inhibition of ] ] may also play a role in the development of isotretinoin-induced depression.<ref name=Bremner2012rev/> A further effect of isotretinoin on the brain involves retinoic acid function in the ], the hormone regulatory centre of the brain and part of the ], a key part of the body's stress response.<ref name=Bremner2012rev/> Other brain regions regulated by ] and potentially disrupted by isotretinoin include the ] and the ].<ref name=Bremner2012rev/> |
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=== Pharmacokinetics and pharmacodynamics === |
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Oral isotretinoin is best absorbed when taken with a high-fat meal because it has a high level of ].<ref name="drugs.com">{{cite web|url=https://www.drugs.com/pro/accutane.html|publisher=U. S. Food and Drug Administration (FDA)|title=FDA information, side effects, and uses / Accutane (isotretinoin)|access-date=20 January 2014}}</ref> The efficacy of isotretinoin doubles when taken after a high-fat meal compared to when taken without food.<ref>{{Cite web|url=https://www.drugs.com/pro/accutane.html#T_2|title=FDA information, side effects, and uses / Accutane (isotretinoin): '''Table 2 Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N=74'''|publisher=U. S. Food and Drug Administration (FDA)|access-date=20 January 2014}}</ref> Due to isotretinoin's molecular relationship to vitamin A, it should not be taken with vitamin A supplements due to the danger of toxicity through cumulative overdosing.<ref>{{cite web|url=https://www.drugs.com/pro/accutane.html#Drug_Interactions|title=FDA information, side effects, and uses / Accutane (isotretinoin): '''Drug Interactions'''|publisher=U. S. Food and Drug Administration (FDA)|access-date=20 January 2014}}</ref> Accutane also negatively interacts with tetracycline, another class of acne drug, and with micro-dosed ('mini-pill') ] preparations, ]/] ('OrthoNovum 7/7/7'), ], ], and systemic ]s. |
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Isotretinoin is primarily (99.9%) bound to plasma proteins, mostly ]. Three metabolites of isotretinoin are detectable in human plasma after oral administration: 4-''oxo''-isotretinoin, retinoid acid (tretinoin), and 4-''oxo''-retinoic acid (4-''oxo''-tretinoin). Isotretinoin also oxidizes, irreversibly, to 4-''oxo''-isotretinoin—which forms its geometric isomer 4-''oxo''-tretinoin. After an orally administered 80 mg dose of liquid suspension <sup>14</sup>C-isotretinoin, <sup>14</sup>C-activity in blood declines with a half-life of 90 hours.<ref name="drugs.com"/> The metabolites of isotretinoin and its conjugates are then excreted in the subject's ] and ] in relatively equal amounts.<ref name="drugs.com"/> After a single, 80 mg oral dose of Isotretinoin to 74 healthy adult subjects under fed conditions, the mean ±SD ] (t<sub>1/2</sub>) of isotretinoin and 4-''oxo''-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively.<ref name="drugs.com"/> After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in people with cystic acne.<ref name="drugs.com"/><!-- this ought to be reworded, not least so it is understandable to the lay reader--> |
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== History == |
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The compound 13-cis retinoic acid was first studied in the 1960s at Roche Laboratories in Switzerland by Werner Bollag as a treatment for skin cancer. Experiments completed in 1971 showed that the compound was likely to be ineffective for cancer but, surprisingly, that it could be useful to treat acne. However, they also showed that the compound was likely to cause birth defects, so in light of the events around ], Roche abandoned the product.<ref name="Abramowitz1988">{{cite news | vauthors = Abramowitz M, Hilts P |title=FDA Eyes Ban on Acne Drug |newspaper=Washington Post |date=23 April 1988 |url=https://www.washingtonpost.com/archive/politics/1988/04/23/fda-eyes-ban-on-acne-drug/c0c5cfae-971f-4007-aa7e-faec39925eb9/ |access-date=14 November 2022}}</ref> In 1979, an article was published reporting the drug's effectiveness as a treatment of cystic and conglobate acne on fourteen patients, thirteen of which experienced complete clearing of their disease.<ref name="Peck"/> In clinical trials, subjects were carefully screened to avoid including women who were or might become pregnant. Roche's ] for isotretinoin for the treatment of acne included data showing that the drug caused birth defects in rabbits.{{medcn|date=December 2022}} The FDA approved the application in 1982.<ref name="Abramowitz1988"/> |
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Scientists involved in the clinical trials published articles warning of birth defects at the same time the drug was launched in the US, but isotretinoin was taken up quickly and widely, both among dermatologists and general practitioners. Cases of birth defects showed up in the first year, leading the FDA to begin publishing case reports and to Roche sending warning letters to doctors and placing warning stickers on drug bottles, and including stronger warnings on the label. Lawsuits against Roche started to be filed. In 1983 the FDA's advisory committee was convened and recommended stronger measures, which the FDA took and were at that time unprecedented: warning blood banks not to accept blood from people taking the drug and adding a warning to the label advising women to start taking contraceptives a month before starting the drug. However, the use of the drug continued to grow, as did the number of babies born with birth defects. In 1985 the label was updated to include a ]. In early 1988 the FDA called for another advisory committee, and FDA employees prepared an internal memo estimating that around 1,000 babies had been born with birth defects due to isotretinoin, that up to around 1,000 miscarriages had been caused, and that between 5,000 and 7,000 women had had abortions due to isotretinoin. The memo was leaked to '']''<ref>{{cite news | title=Anti-Acne Drug Faulted in Birth Defects | website=] | date=22 April 1988 | url=https://www.nytimes.com/1988/04/22/us/anti-acne-drug-faulted-in-birth-defects.html | access-date=2 December 2022}}</ref> a few days before the meeting, leading to a storm of media attention. In the committee meeting, dermatologists and Roche each argued to keep the drug on the market but to increase education efforts; pediatricians and the ] (CDC) argued to withdraw the drug from the market. The committee recommended restricting physicians who could prescribe the drug and requiring a second opinion before it could be prescribed. The FDA, believing it did not have authority under the law to restrict who had the right to prescribe the drug, kept the drug on the market but took further unprecedented measures: it required Roche to make warnings yet more visible and graphic, provide doctors with ] forms to be used when prescribing the drug, and to conduct follow up studies to test whether the measures were reducing exposure of pregnant women to the drug. Roche implemented those measures, and offered to pay for contraception counseling and pregnancy testing for women prescribed the drug; the program was called the "Pregnancy Prevention Program". |
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A CDC report published in 2000,<ref>{{cite journal | title = Accutane-exposed pregnancies--California, 1999 | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 49 | issue = 2 | pages = 28–31 | date = January 2000 | pmid = 10680601 | doi = | url = <!-- Official URL --> https://www.cdc.gov/mmwr/PDF/wk/mm4902.pdf | author1 = Centers for Disease Control Prevention (CDC) }}</ref> showed problems with the Pregnancy Prevention Program and showed that the increase in prescriptions was from off-label use, and prompted Roche to revamp its program, renaming it the "Targeted Pregnancy Prevention Program" and adding label changes like requirements for two pregnancy tests, two kinds of contraception, and for doctors to provide pharmacists with prescriptions directly; providing additional educational materials, and providing free pregnancy tests. The FDA had another advisory meeting in late 2000 that again debated how to prevent pregnant women from being exposed to the drug; dermatologists testified about the remarkable efficacy of the drug, the psychological impact of acne, and demanded autonomy to prescribe the drug; others argued that the drug be withdrawn or much stricter measures be taken. In 2001 the FDA announced a new regulatory scheme called SMART (the System to Manage Accutane Related Teratogenicity) that required Roche to provide defined training materials to doctors, and for doctors to sign and return a letter to Roche acknowledging that they had reviewed the training materials, for Roche to then send stickers to doctors, which doctors would have to place on prescriptions they give people after they have confirmed a negative pregnancy test; prescriptions could only be written for 30 days and could not be renewed, thus requiring a new pregnancy test for each prescription.<ref>{{cite journal | vauthors = Choi JS, Koren G, Nulman I | title = Pregnancy and isotretinoin therapy | journal = CMAJ | volume = 185 | issue = 5 | pages = 411–413 | date = March 2013 | pmid = 23296582 | pmc = 3602257 | doi = 10.1503/cmaj.120729 }}</ref> |
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In February 2002, Roche's patents for isotretinoin expired, and there are now many other companies selling cheaper generic versions of the drug. On 29 June 2009, ], the original creator and distributor of isotretinoin, officially discontinued both the manufacture and distribution of their '''Accutane''' brand in the ] due to what the company described as business reasons related to low market share (below 5%), coupled with the high cost of defending personal injury lawsuits brought by some people who took the drug.<ref>{{cite news | url = https://www.latimes.com/nation/la-sci-accutane7-2009nov07-story.html | newspaper = ] | title = New study may deal final blow to acne drug Accutane |date=7 November 2009 | vauthors = Roan S }}</ref> Roche USA continues to defend Accutane and claims to have treated over 13{{nbsp}}million people since its introduction in 1982. F. Hoffmann-La Roche Ltd. apparently will continue to manufacture and distribute '''Roaccutane''' outside of the United States.<ref>{{cite press release | title = Roche Discontinues and Plans to Delist Accutane in the U.S. | publisher = ] | date = 29 June 2009 | url = http://www.gene.com/gene/products/information/accutane/ | access-date = 12 November 2010 | url-status = dead | archive-url = https://web.archive.org/web/20091108053218/http://www.gene.com/gene/products/information/accutane/ | archive-date = 8 November 2009 }}</ref> |
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Among others, actor ] sued Roche over allegedly Accutane-related disease that resulted in the removal of his ].<ref>{{cite news| url=https://www.bloomberg.com/news/2011-03-10/roche-s-accutane-caused-tragedy-for-actor-brian-dennehy-says.html | work=Bloomberg | vauthors = Feeley J | title=Roche Accutane Acne Drug Caused 'Tragedy' for Actor, Brian Dennehy Says | date = 11 March 2011}}</ref> The jury, however, decided that James Marshall had a pre-existing bowel disease.<ref name="urlIts Curtains On Actors Accutane Lawsuit | Pharmalot">{{cite web | url = http://www.pharmalive.com/its-curtains-actors-accutane-lawsuit | title = It's Curtains On Actor's Accutane Lawsuit | author = Silverman E | date = 4 November 2011 | work = Pharmalot | publisher = UBM Canon }}{{Dead link|date=February 2022 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> |
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Several trials over inflammatory bowel disease claims have been held in the United States, with many of them resulting in multimillion-dollar judgments against the makers of isotretinoin.<ref>{{cite news |vauthors = Voreacos D |date=30 May 2007 |url=https://www.washingtonpost.com/wp-dyn/content/article/2007/05/29/AR2007052901946.html |title=Roche Found Liable in First Of 400 Suits Over Accutane |agency=Bloomberg News |access-date=30 April 2012 |newspaper=]}}</ref> |
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==Society and culture== |
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===Brands=== |
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As of 2017, isotretinoin was marketed under many brand names worldwide: A-Cnotren, Absorica, Accuran, Accutane, Accutin, Acne Free, Acnecutan, Acnegen, Acnemin, Acneone, Acneral, Acnestar, Acnetane, Acnetin A, Acnetrait, Acnetrex, Acnogen, Acnotin, Acnotren, Acretin, Actaven, Acugen, Acutret, Acutrex, Ai Si Jie, Aisoskin, Aknal, Aknefug Iso, Aknenormin, Aknesil, Aknetrent, Amnesteem, Atlacne, Atretin, Axotret, Casius, Ciscutan, Claravis, Contracné, Curacne, Curacné, Curakne, Curatane, Cuticilin, Decutan, Dercutane, Effederm, Epuris, Eudyna, Farmacne, Flexresan, Flitrion, I-Ret, Inerta, Inflader, Inotrin, Isac, Isdiben, Isoacne, Isobest, Isocural, Isoderm, Isoface, IsoGalen, Isogeril, Isolve, Isoprotil, Isoriac, Isosupra, Isosupra Lidose, Isotane, Isotina, Isotinon, Isotren, Isotret, Isotretinoin, Isotretinoina, Isotretinoína, Isotretinoine, Isotretinoïne, Isotrétinoïne, Isotretinoinum, Isotrex, Isotrin, Isotroin, Izotek, Izotziaja, Lisacne, Locatret, Mayesta, Medinac, Myorisan, Neotrex, Netlook, Nimegen, Noitron, Noroseptan, Novacne, Oralne, Oraret, Oratane, Piplex, Policano, Procuta, Reducar, Retacnyl, Retin A, Roaccutan, Roaccutane, Roacnetan, Roacta, Roacutan, Rocne, Rocta, Sotret, Stiefotrex, Tai Er Si, Teweisi, Tretin, Tretinac, Tretinex, Tretiva, Tufacne, Zenatane, Zerocutan, Zonatian ME, and Zoretanin.<ref name=brands>{{cite web|title=Isotretinoin international brands|url=https://www.drugs.com/international/isotretinoin.html|publisher=Drugs.com|access-date=1 June 2017}}</ref> |
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The topical ] ] combines the antibiotic ] with isotretinoin and has been marketed under the brand names Isotrex Eritromicina, Isotrexin, and Munderm.<ref name=brands/> |
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== References == |
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{{reflist}} |
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{{Carotenoids}} |
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{{Acne agents}} |
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{{Retinoid receptor modulators}} |
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{{Portal bar | Medicine}} |
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