Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Dolutegravir: Difference between pages

{{Short description|Chemical compound}}

{{Use dmy dates|date=March 2024}}

{{Drugbox

| Verifiedfields = changed

| verifiedrevid = 477389515

| image = Dolutegravir structure.svg

| width = 250

| alt =

| image2 = Dolutegravir ball-and-stick model.png

| alt2 =

<!-- Clinical data -->

| tradename = Tivicay, Tivicay PD

| Drugs.com = {{drugs.com|monograph|dolutegravir-sodium}}

| MedlinePlus = a613043

| DailyMedID = Dolutegravir

| pregnancy_AU = B1

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Dolutegravir (Tivicay) Use During Pregnancy | website=Drugs.com | date=16 October 2018 | url=https://www.drugs.com/pregnancy/dolutegravir.html | access-date=13 February 2020}}</ref>

| routes_of_administration = [[Oral administration|By mouth]]

| class =

| ATC_prefix = J05

| ATC_suffix = AJ03

| ATC_supplemental = {{ATC|J05|AR13}} {{ATC|J05|AR21}}

<!-- Legal status -->

| legal_AU = S4

| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2014 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014 | access-date=10 April 2023}}</ref>

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title=Drug and medical device highlights 2018: Helping you maintain and improve your health | website=[[Health Canada]] | date=14 October 2020 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/drug-medical-device-highlights-2018.html| access-date=17 April 2024}}</ref>

| 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="Tivicay FDA label" />

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Tivicay EPAR" />

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = Rx-only

<!-- Pharmacokinetic data -->

| bioavailability = n/a<ref name="Tivicay FDA label">{{cite web | title=Tivicay- dolutegravir sodium tablet, film coated | website=DailyMed | date=24 October 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=63df5af3-b8ac-4e76-9830-2dbb340af922 | access-date=13 February 2020}}</ref>

| protein_bound = ≥98.9%

| metabolism = [[UDP glucuronosyltransferase 1 family, polypeptide A1|UGT1A1]] and [[CYP3A]]

| metabolites =

| onset =

| elimination_half-life = ~14 hours

| duration_of_action =

| excretion = Feces (53%) and urine (18.9%)

<!-- Identifiers -->

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 1051375-16-6

| CAS_supplemental =

| PubChem = 54726191

| IUPHAR_ligand = 7365

| DrugBank_Ref =

| DrugBank = DB08930

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 25051637

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = DKO1W9H7M1

| KEGG_Ref =

| KEGG = D10066

| ChEBI_Ref =

| ChEBI = 76010

| ChEMBL = 1229211

| PDB_ligand = DLU

| synonyms = GSK572, S-349572

<!-- Chemical and physical data -->

| IUPAC_name = (4''R'',12a''S'')-''N''-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2''H''-pyrido[1',2':4,5]pyrazino[2,1-''b''] [1,3]oxazine-9-carboxamide

| C=20 | H=19 | F=2 | N=3 | O=5

| SMILES = C[C@@H]1CCO[C@@H]2N1C(=O)c3c(c(=O)c(cn3C2)C(=O)NCc4ccc(cc4F)F)O

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI_comment =

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

<!-- Definition and medical uses -->

'''Dolutegravir''' ('''DTG'''), sold under the brand name '''Tivicay''', is an [[antiretroviral medication]] used, together with other medication, to treat [[HIV/AIDS]].<ref name=BNF69>{{cite book|title=British national formulary : BNF 69|date=2015|publisher=British Medical Association|isbn=9780857111562|page=429|edition=69}}</ref> It may also be used, as part of [[post exposure prophylaxis]], to prevent HIV infection following potential exposure.<ref name=AHFS2019/> It is taken by mouth.<ref name=BNF69/>

<!-- Side effects and mechanism -->

Common side effects include trouble sleeping, feeling tired, [[diarrhea]], [[high blood sugar]], and headache.<ref name=AHFS2019/> Severe side effects may include [[allergic reactions]] and [[liver problems]].<ref name=AHFS2019/> There are tentative concerns that use during [[pregnancy]] can result in harm to the baby.<ref name=AHFS2019>{{cite web |title=Dolutegravir Sodium Monograph for Professionals |url=https://www.drugs.com/monograph/dolutegravir-sodium.html |website=Drugs.com |access-date=20 April 2019 |language=en}}</ref> It is unclear if use during [[breastfeeding]] is safe.<ref name=AHFS2019/> Dolutegravir is an [[HIV integrase strand transfer inhibitor]] which blocks the functioning of [[HIV integrase]] which is needed for [[viral replication]].<ref name=AHFS2019/>

<!-- History and culture -->

Dolutegravir was approved for medical use in the United States in 2013.<ref name=AHFS2019 /> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> [[Abacavir/dolutegravir/lamivudine]], a combination with [[abacavir]] and [[lamivudine]] is also available.<ref name=AHFS2019/><ref name="Ciccullo_2020">{{cite journal | vauthors = Ciccullo A, Baldin G, Borghetti A, Di Giambenedetto S | title = Dolutegravir plus lamivudine for the treatment of HIV-1 infection | journal = Expert Review of Anti-infective Therapy | volume = 18 | issue = 4 | pages = 279–292 | date = April 2020 | pmid = 32067525 | doi = 10.1080/14787210.2020.1729742 | s2cid = 211160876 }}</ref><ref name="Patel_2021">{{cite journal | vauthors = Patel R, Evitt L, Mariolis I, Di Giambenedetto S, d'Arminio Monforte A, Casado J, Cabello Úbeda A, Hocqueloux L, Allavena C, Barber T, Jha D, Kumar R, Kamath RD, Vincent T, van Wyk J, Koteff J | display-authors = 6 | title = HIV Treatment with the Two-Drug Regimen Dolutegravir Plus Lamivudine in Real-world Clinical Practice: A Systematic Literature Review | journal = Infectious Diseases and Therapy | volume = 10| issue = 4| date = August 2021 | pages = 2051–2070 | pmid = 34426899 | doi = 10.1007/s40121-021-00522-7 | pmc = 8572911 }}</ref> As of 2019, the [[World Health Organization]] (WHO) recommends DTG as the first- and second-line treatment for all persons with HIV.<ref>{{Cite press release |url=https://www.who.int/news-room/detail/22-07-2019-who-recommends-dolutegravir-as-preferred-hiv-treatment-option-in-all-populations|title=WHO recommends dolutegravir as preferred HIV treatment option in all populations|website=[[World Health Organization]]|access-date=22 July 2019}}</ref>

== Medical use ==

Dolutegravir is approved for use in a broad population of HIV-infected patients. It can be used to treat HIV-infected adults who have never taken HIV therapy (treatment-naïve) and HIV-infected adults who have previously taken HIV therapy (treatment-experienced), including those who have been treated with other integrase strand transfer inhibitors. Tivicay is also approved for children ages 12 years and older weighing at least 40 kilograms (kg) who are treatment-naïve or treatment-experienced but have not previously taken other integrase strand transfer inhibitors.<ref name="fda.gov">{{cite web | title = FDA approves new drug to treat HIV infection | website = [[Food and Drug Administration]] | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm | date = 12 August 2013 | archive-url = https://web.archive.org/web/20140208194050/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm | archive-date = 8 February 2014 | url-status = dead }}</ref>

In the European Union it is indicated, in combination with other anti-retroviral medicinal products, for the treatment of Human Immunodeficiency Virus (HIV) infected adults, adolescents and children above six years of age.<ref name="Tivicay EPAR" />

In June 2020, the indication for dolutegravir in the US was updated to include children at least four weeks old and weighing at least 3&nbsp;kg (6.61 pounds).<ref name="FDA PR 20200612">{{cite press release | title=FDA Approves Drug to Treat Infants and Children with HIV | website=U.S. [[Food and Drug Administration]] (FDA) | date=12 June 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-drug-treat-infants-and-children-hiv | access-date=12 June 2020}}</ref>

==Adverse effects==

Common side effects of dolutegravir in clinical trials included insomnia and headache. Serious side effects included allergic reactions and abnormal liver function in patients who were also infected with hepatitis B or C.<ref>{{cite web | title=U.S. FDA approves GlaxoSmithKline's HIV drug Tivicay | website=Reuters | date=12 August 2013 | url=https://www.reuters.com/article/us-glaxosmithkline-hivdrug-idUSBRE97B0WU20130812 | access-date=13 February 2020}}</ref> The package insert warns against a mean rise in serum creatinine of 0.11&nbsp;mg/dL due to inhibition of tubular secretion of creatinine and does not affect [[renal function|GFR]].<ref name="Tivicay FDA label" />

===Pregnancy===

There are tentative concerns that use during [[pregnancy]] can result in harm to the baby.<ref name=AHFS2019/> Effective [[birth control]] is thus recommended while on dolutegravir, with pregnancy testing before starting treatment.<ref name=EMA2019/> Use during the first trimester should only occur if there is no alternative.<ref name=EMA2019>{{Cite web|url=https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-1-4-october-2018|title=Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 1-4 October 2018|date=5 October 2018|website=[[European Medicines Agency]] (EMA) }}</ref>

==History==

In February 2013, the U.S. [[Food and Drug Administration]] (FDA) announced that it would fast track dolutegravir's approval process.<ref>{{cite news |title=GSK wins priority status for new HIV drug in U.S|url=https://news.yahoo.com/gsk-wins-priority-status-hiv-drug-u-140116042--finance.html|archive-url=https://web.archive.org/web/20130219034722/http://news.yahoo.com/gsk-wins-priority-status-hiv-drug-u-140116042--finance.html|url-status=dead|archive-date=19 February 2013|newspaper=[[Reuters]]|date=16 February 2013|access-date=18 February 2013}} </ref> On 13 August 2013, dolutegravir was approved for medical use in the United States.<ref>{{cite web | title=Drug Approval Package: Tivicay (dolutegravir) Tablets NDA #204790 | website=U.S. [[Food and Drug Administration]] (FDA) | date=13 September 2013 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204790Orig1s000TOC.cfm | access-date=12 June 2020}}</ref> On 4 November 2013, dolutegravir was approved by Health Canada.<ref>{{cite news|title=ViiV Healthcare receives approval for Tivicay (dolutegravir) in Canada for the treatment of HIV|url=http://www.viivhealthcare.ca/com/pdf/news-releases/en/Tivicay_Media_Release_English.pdf|access-date=11 November 2013|url-status=dead|archive-url=https://web.archive.org/web/20131112012034/http://www.viivhealthcare.ca/com/pdf/news-releases/en/Tivicay_Media_Release_English.pdf|archive-date=12 November 2013}}</ref> On 16 January 2014, it was approved by the European Commission for use throughout the European Union.<ref name="Tivicay EPAR">{{cite web | title=Tivicay EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/tivicay | access-date=13 February 2020}}</ref>

In 2019, a [[Fixed-dose combination (antiretroviral)|triple-combination therapy]], with dolutegravir replacing [[efavirenz]], was introduced as the first-line treatment for all people (pregnant excluded) with HIV by the [[South African Government]] (public) sector.{{medcn|date=February 2020}}

In June 2020, dolutegravir was approved in the US with an indication to treat HIV-1 infection in children at least four weeks old and weighing at least 3&nbsp;kg (6.61 pounds) in combination with other antiretroviral treatments.<ref name="FDA PR 20200612" /> It is intended to treat children at least 4 weeks old and 3&nbsp;kg who have never been treated for HIV or who have been treated, but not with an integrase strand transferase inhibitor (INSTI) class drug.<ref name="FDA PR 20200612" /><ref>{{cite press release | title=ViiV Healthcare announces US FDA approval of the first-ever dispersible tablet formulation of dolutegravir, Tivicay PD, a once-daily treatment for children living with HIV | website=GSK | url=https://www.gsk.com/en-gb/media/press-releases/viiv-healthcare-announces-us-fda-approval-of-the-first-ever-dispersible-tablet-formulation-of-dolutegravir/ | access-date=12 June 2020}}</ref>

The U.S. [[Food and Drug Administration]] (FDA) granted the approval of Tivicay and Tivicay PD to ViiV Healthcare.<ref name="FDA PR 20200612" />

==References==

{{reflist}}

{{Antiretroviral drug}}

{{Portal bar | Medicine | Viruses }}

[[Category:Drugs developed by GSK plc]]

[[Category:Hepatotoxins]]

[[Category:Integrase inhibitors]]

[[Category:Organofluorides]]

[[Category:World Health Organization essential medicines]]

[[Category:Wikipedia medicine articles ready to translate]]