View source for Chemistry:Baloxavir marboxil

{{Short description|Antiviral medication}}
{{Infobox drug
| drug_name         = Baloxavir marboxil
| INN               =
| type              = <!-- empty -->
| image             = Baloxavir marboxil.svg
| width             = 200
| alt               =
| image2            =
| width2            =
| alt2              =
| caption           =

<!-- Clinical data -->
| pronounce         =
| tradename         = Xofluza
| Drugs.com         = {{drugs.com|monograph|baloxavir-marboxil}}
| MedlinePlus       = a618062
| licence_CA        = <!-- Health Canada may use generic or brand name (generic name preferred) -->
| licence_EU        = yes
| DailyMedID        = Baloxavir_marboxil
| licence_US        = Xofluza
| pregnancy_AU      = B3
| pregnancy_AU_comment = <ref name="Xofluza APMDS">{{cite web | title=Xofluza Australian prescription medicine decision summary | website=Therapeutic Goods Administration (TGA) | date=2 March 2020 | url=https://www.tga.gov.au/apm-summary/xofluza | access-date=16 August 2020 | archive-date=13 March 2020 | archive-url=https://web.archive.org/web/20200313132100/https://www.tga.gov.au/apm-summary/xofluza | url-status=live }}</ref>
| pregnancy_category=
| routes_of_administration = [[Medicine:Oral administration|By mouth]]
| class             =
| ATCvet            =
| ATC_prefix        = J05
| ATC_suffix        = AX25
| ATC_supplemental  =

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = <ref name="Xofluza APMDS" />
| 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=Xofluza Product information | website=Health Canada | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=98624 | access-date=29 May 2022 | archive-date=12 August 2022 | archive-url=https://web.archive.org/web/20220812131821/https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=98624 | url-status=live }}</ref><ref>{{cite web | title=Summary Basis of Decision (SBD) for Xofluza | website=[[Organization:Health Canada|Health Canada]] | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00475&lang=en | access-date=29 May 2022 | archive-date=31 May 2022 | archive-url=https://web.archive.org/web/20220531043251/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00475&lang=en | url-status=live }}</ref>
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment = <ref name="Xofluza FDA label" />
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Xofluza EPAR" /><ref>{{cite web | title=Xofluza Product information | website=Union Register of medicinal products | url=https://ec.europa.eu/health/documents/community-register/html/h1500.htm | access-date=3 March 2023}}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment =
| legal_status      = Rx-only

<!-- Pharmacokinetic data -->
| bioavailability   =
| protein_bound     =
| metabolism        =
| metabolites       =
| onset             =
| elimination_half-life =
| duration_of_action =
| excretion         =

<!-- Identifiers -->
| CAS_number        = 1985606-14-1
| CAS_supplemental  =
| PubChem           = 124081896
| IUPHAR_ligand     =
| DrugBank          = DB13997
| ChemSpiderID      = 59718643
| UNII              = 505CXM6OHG
| KEGG              = D11021
| ChEBI             =
| ChEMBL            =
| NIAID_ChemDB      =
| PDB_ligand        =
| synonyms          = BXM (S-033188), BXA (S-033447)

<!-- Chemical and physical data -->
| IUPAC_name        = ({(12a''R'')-12-[(11''S'')-7,8-Difluoro-6,11-dihydrodibenzo[''b'',''e'']thiepin-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1''H''-[1,4]oxazino[3,4-''c'']pyrido[2,1-''f''] [1,2,4]triazin-7-yl}oxy)methyl methyl carbonate
| C=27 | H=23 | N=3| F=2 | O=7 | S=1
| SMILES            = O=C(OCOC(C(C=C1)=O)=C(N1N([C@@H]2C3=CC=CC=C3SCC4=C(F)C(F)=CC=C24)[C@@]5([H])N6CCOC5)C6=O)OC
| StdInChI          = 1S/C27H23F2N3O7S/c1-36-27(35)39-14-38-25-19(33)8-9-31-24(25)26(34)30-10-11-37-12-21(30)32(31)23-15-6-7-18(28)22(29)17(15)13-40-20-5-3-2-4-16(20)23/h2-9,21,23H,10-14H2,1H3/t21-,23+/m1/s1
| StdInChI_comment  =
| StdInChIKey       = RZVPBGBYGMDSBG-GGAORHGYSA-N
| density           =
| density_notes     =
| melting_point     =
| melting_high      =
| melting_notes     =
| boiling_point     =
| boiling_notes     =
| solubility        =
| sol_units         =
| specific_rotation =
}}

'''Baloxavir marboxil''', sold under the brand name '''Xofluza''', is an antiviral medication for treatment of [[Biology:Influenza A virus|influenza A]] and [[Biology:Influenza B virus|influenza B]].<ref name="Xofluza FDA label" /> It was approved for medical use both in Japan and in the United States in 2018,<ref name="FDA PR 20181024">{{cite press release | title=FDA approves new drug to treat influenza | publisher=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | date=24 October 2018 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treat-influenza | archive-url=https://web.archive.org/web/20191024055423/https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treat-influenza | archive-date=24 October 2019 | url-status=live | access-date=23 October 2019}} {{PD-notice}}</ref><ref name="FDA approval 2018" /><ref name="FDA approval 2019" /> and is taken as a single dose [[Medicine:Oral administration|by mouth]].<ref name="Xofluza FDA label" /> It may reduce the duration of flu symptoms by about a day, but is prone to selection of resistant mutants that render it ineffectual.<ref>{{Cite web|title=Baloxavir Marboxil for Uncomplicated Influenza: Mechanism of Action & Side Effects|url=https://en.huatengsci.com/article/106.html|website=Huateng Pharma|access-date=29 May 2020|archive-date=24 February 2021|archive-url=https://web.archive.org/web/20210224181632/http://en.huatengsci.com/article/106.html|url-status=live}}</ref>

Baloxavir marboxil was developed as a [[Chemistry:Prodrug|prodrug]] strategy, with its metabolism releasing the active agent, '''baloxavir acid''' (BXA). Baloxavir acid then functions as [[Biology:Enzyme inhibitor|enzyme inhibitor]], targeting the influenza virus' [[Biology:Five-prime cap|cap]]-dependent [[Biology:Ribonuclease|endonuclease]] activity, used in "[[Biology:Cap snatching|cap snatching]]" by the [[Biology:Orthomyxoviridae|virus']] [[Biology:Polymerase|polymerase]] complex, a process essential to its life-cycle.<ref>{{cite journal |vauthors=Noshi T, Kitano M, Taniguchi K, Yamamoto A, Omoto S, Baba K, Hashimoto T, Ishida K, Kushima Y, Hattori K, Kawai M, Yoshida R, Kobayashi M, Yoshinaga T, Sato A, Okamatsu M, Sakoda Y, Kida H, Shishido T, Naito A |display-authors=6 |title=In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit |journal=Antiviral Res. |volume=160 |pages=109–117 |date=December 2018 |pmid=30316915 |doi=10.1016/j.antiviral.2018.10.008 | doi-access = free | title-link = doi }}</ref>

The most common side effects of baloxavir marboxil include [[Medicine:Diarrhea|diarrhea]], [[Medicine:Bronchitis|bronchitis]], nausea, [[Medicine:Sinusitis|sinusitis]], and [[Medicine:Headache|headache]].<ref name="FDA PR 20201123" />

The US [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) considers baloxavir marboxil to be a [[Medicine:First-in-class medication|first-in-class medication]].<ref>{{cite report | title=New Drug Therapy Approvals 2018 | publisher=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | date=January 2019 | url=https://www.fda.gov/media/120357/download | format=PDF | access-date=16 September 2020 | archive-date=17 September 2020 | archive-url=https://web.archive.org/web/20200917055627/https://www.fda.gov/media/120357/download | url-status=live }} {{PD-notice}}</ref>

==Medical uses==
Baloxavir marboxil is an influenza medication, an antiviral,<ref name=AHFS2019>{{cite web | title=Baloxavir Marboxil Monograph for Professionals | website=Drugs.com | publisher=American Society of Health-System Pharmacists | date=19 August 2019 | url=https://www.drugs.com/monograph/baloxavir-marboxil.html | access-date=9 January 2020 | archive-date=7 October 2019 | archive-url=https://web.archive.org/web/20191007182411/https://www.drugs.com/monograph/baloxavir-marboxil.html | url-status=live }}</ref><ref name="Xofluza FDA label">{{cite web | title=Xofluza- baloxavir marboxil tablet, film coated | website=DailyMed | date=28 October 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e49e1a61-1b7c-4be5-ac84-af6240b511e7 | access-date=9 January 2020 | archive-date=28 October 2020 | archive-url=https://web.archive.org/web/20201028141815/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e49e1a61-1b7c-4be5-ac84-af6240b511e7 | url-status=live }}</ref> for individuals who are twelve years of age or older,<ref name="Xofluza EPAR" /><ref name=AHFS2019 /> that have presented symptoms of this infection for no more than 48 hours.<ref name="Xofluza EPAR" /><ref name=AHFS2019 /><ref name="FDA Snapshot">{{cite web | vauthors=((Food and Drug Administration)) | date=23 July 2019 | title=Drug Trial Snapshot: Xofluza | publisher=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | url=http://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-xofluza | access-date=7 January 2020 | archive-date=12 December 2019 | archive-url=https://web.archive.org/web/20191212135516/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-xofluza | url-status=live }} {{PD-notice}}</ref> The efficacy of baloxavir marboxil administered after 48 hours has not been tested.<ref name=AHFS2019 />

In October 2019, the FDA approved an updated [[Medicine:Indication|indication]] for the treatment of acute, uncomplicated influenza in people twelve years of age and older at risk of influenza complications.<ref name="Xofluza FDA label" /><ref name="FDA approval 2019" />

In November 2020, the FDA approved an updated indication to include post-exposure prevention of influenza (flu) for people twelve years of age and older after contact with an individual who has the flu.<ref name="Xofluza FDA label" /><ref name="FDA PR 20201123" />

In August 2022, the FDA approved an updated indication to include post-exposure prevention of influenza (flu) for people five years of age and older after contact with an individual who has the flu.<ref name="Xofluza FDA label" /><ref>{{cite press release | title=Genentech Announces FDA Approval of Xofluza to Treat Influenza in Children Aged Five and Older | publisher=Genentech | via=Business Wire | date=11 August 2022 | url=https://www.businesswire.com/news/home/20220815005009/en/Genentech-Announces-FDA-Approval-of-Xofluza-to-Treat-Influenza-in-Children-Aged-Five-and-Older | access-date=11 August 2022 | archive-date=12 August 2022 | archive-url=https://web.archive.org/web/20220812131831/https://www.businesswire.com/news/home/20220815005009/en/Genentech-Announces-FDA-Approval-of-Xofluza-to-Treat-Influenza-in-Children-Aged-Five-and-Older | url-status=live }}</ref>

In the EU, baloxavir marboxil is indicated for the treatment of uncomplicated influenza and for post-exposure prophylaxis of influenza in individuals aged twelve years of age and older.<ref name="Xofluza EPAR" />

=== Available forms ===
Baloxavir marboxil is available in tablet form and as granules for mixing in water.<ref name="FDA PR 20201123" />

===Resistance===
In 2.2% of baloxavir recipients in the Phase II trial and in about 10% of baloxavir recipients in the Phase III trial, the infecting influenza strain had [[Biology:Resistance mutation (virology)|acquired resistance]] to the drug, due to variants of the polymerase protein displaying substitutions of isoleucine-38, specifically, the I38T, I38M, or I38F mutations.<ref name=nejm/> There is continuing research into and clinical concern over the resistance appearing in recipients, in response to treatment with this drug.<ref>{{Cite web|url=https://www.fiercepharma.com/pharma/roche-s-flu-med-xofluza-drives-drug-resistance-and-may-be-a-bad-choice-for-kids-study-says|title=Roche's flu med Xofluza drives drug resistance and may be a bad choice for kids, study says|website=FiercePharma|date=26 November 2019|access-date=8 January 2020|archive-date=25 November 2020|archive-url=https://web.archive.org/web/20201125084526/https://www.fiercepharma.com/pharma/roche-s-flu-med-xofluza-drives-drug-resistance-and-may-be-a-bad-choice-for-kids-study-says|url-status=live}}</ref><ref>{{Cite press release|url=https://www.eurekalert.org/pub_releases/2019-11/uow-nfd111919.php|title=New flu drug drives drug resistance in influenza viruses|website=EurekAlert|access-date=8 January 2020|archive-date=16 January 2021|archive-url=https://web.archive.org/web/20210116152733/https://eurekalert.org/pub_releases/2019-11/uow-nfd111919.php|url-status=live}}</ref><ref>{{Cite journal|title=Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets|vauthors=Imai M, Yamashita M, Sakai-Tagawa Y, Iwatsuki-Horimoto K, Kiso M, Murakami J, Yasuhara A, Takada K, Ito M, Nakajima N, Takahashi K, Lopes TJ, Dutta J, Khan Z, Kriti D, van Bakel H, Tokita A, Hagiwara H, Izumida N, Kuroki H, Nishino T, Wada N, Koga M, Adachi E, Jubishi D, Hasegawa H, Kawaoka Y |display-authors=6 |date=January 2020|journal=Nature Microbiology|volume=5|issue=1|pages=27–33|doi=10.1038/s41564-019-0609-0|pmid=31768027 |s2cid=208279215 }}</ref>

== Contraindications ==
Baloxavir marboxil should not be co-administered with dairy products, calcium-fortified beverages, or laxatives, antacids, or oral supplements containing calcium, iron, magnesium, selenium, aluminum or zinc.<ref name="FDA PR 20201123" />

==Side effects==
Common side effects following the single dose administration of baloxavir marboxil include diarrhea, bronchitis, common cold, headache, and nausea.<ref name="Xofluza FDA label" /><ref name="FDA Snapshot" /><ref name="FDA PR 20181024" /> Adverse events were reported in 21% of people who received baloxavir, 25% of those receiving placebo, and 25% of oseltamivir.<ref name=nejm/>

== Mechanism of action ==
Baloxavir marboxil is an influenza therapeutic agent, specifically, an [[Biology:Enzyme inhibitor|enzyme inhibitor]] targeting the influenza virus' [[Biology:Five-prime cap|cap]]-dependent [[Biology:Ribonuclease|endonuclease]] activity, one of the activities of the virus polymerase complex.<ref>{{cite journal | vauthors = Eisfeld AJ, Neumann G, Kawaoka Y | title = At the centre: influenza A virus ribonucleoproteins | journal = Nature Reviews. Microbiology | volume = 13 | issue = 1 | pages = 28–41 | date = January 2015 | pmid = 25417656 | pmc = 5619696 | doi = 10.1038/nrmicro3367 }}</ref><!-- TWO SENTENCES REMOVED HERE—ONE IRRELEVANT, ON DOSING, AND THE SECOND, EARLIER, PUT FORWARD [[Chemistry:Pharmacodynamics|pharmacodynamics]] AND OTHERWISE RESTATED THE OPENING SENTENCE, AND SO WAS SIMPLY WRONG, AND UNNECESSARY. --> In particular, it inhibits a process known as [[Biology:Cap snatching|cap snatching]],{{medcn|date=September 2020}} by which the virus derives short, capped [[Biology:Primer (molecular biology)|primer]]s from host cell RNA transcripts, which it then uses for polymerase-catalyzed synthesis of its needed viral [[Biology:MRNA|mRNA]]s.<ref name=OHanlon2019>{{cite journal | vauthors = O'Hanlon R, Shaw ML | title = Baloxavir marboxil: the new influenza drug on the market | journal = Current Opinion in Virology | volume = 35 | pages = 14–18 | date = April 2019 | pmid = 30852344 | doi = 10.1016/j.coviro.2019.01.006 | s2cid = 73726080 }}</ref> A polymerase subunit binds to the host pre-mRNAs at their 5' caps, then the polymerase's [[Biology:Endonuclease|endonuclease]] activity catalyzes its cleavage "after 10–13 nucleotides".{{medcn|date=September 2020}} As such, its mechanism is distinct from neuraminidase inhibitors such as [[Chemistry:Oseltamivir|oseltamivir]] and [[Chemistry:Zanamivir|zanamivir]].<ref name=OHanlon2019/>

==Chemistry==
Baloxavir marboxil is a substituted pyridone derivative of a [[Chemistry:Polycyclic compound|polycyclic]] family, whose chemical synthesis has been reported in a number of ways by the company discovering it, Shionogi and Co. of Japan (as well as others); the Shionogi reports have appeared several times in the Japanese patent literature between 2016 and 2019, providing insight into possible industrial synthetic routes that may be in use.<ref>{{cite patent | inventor = Okamoto K, Ueno T, Hato Y, Hakogi T, Majima S | title = Method for stereoselective preparation of substituted polycyclic pyridone derivative. | assign1 = Shionogi & Co., Ltd., Japan. | country = WO | number = 2019070059 | pubdate = 2019 }}</ref><ref>{{cite patent | inventor = Kawai M, Tomita K, Akiyama T, Okano A, Miyagawa M | title = Pharmaceutical composition containing polycyclic pyridone derivatives as cap-dependent endonuclease (CEN) inhibitors. | assign1 = Shionogi and Co., Ltd., Japan. | country = JPWO | number = 2018030463 <!-- 6249434 --> | pubdate = 2017 }}</ref><ref>{{cite patent | inventor = Shibahara S, Fukui N, Maki T | title = Polycyclic pyridone derivative, crystal and preparation method thereof. | assign1 = Shionogi and Co., Ltd., Japan. | country = JPWO | number = 2017221869 <!-- 6212678 --> | pubdate = 2017 }}</ref><ref>{{cite patent | inventor = Kawai M, Tomita K, Akiyama T, Okano A, Miyagawa M | title = Preparation of polycyclic pyridone derivatives as cap-dependent endonuclease (CEN) inhibitors and prodrugs thereof. | assign1 = Shionogi and Co., Ltd., Japan | country = JPWO | number = 2016175224 <!-- 5971830 --> | pubdate = 2016 }}</ref><ref>{{cite patent | inventor = Zhu X, Jiang W | title = Process for preparation of substituted polycyclic carbamoylpyridone derivative and its prodrug. | country = CN | number = 108440564 | pubdate = 2018 }}</ref>

[[File:Baloxavir.svg|thumb|Baloxavir acid (BXA) or simply baloxavir, the active moiety<ref>{{cite web | title = Baloxavir | work = PubChem | publisher = U.S. National Library of Medicine | url = https://pubchem.ncbi.nlm.nih.gov/compound/124081876 | id = CID 124081876 | access-date = 28 July 2021 }}</ref>]]

Baloxavir marboxil (BXM) is a prodrug whose active agent, baloxavir acid (BXA) is released rapidly ''in vivo'', as the hydrolysis of baloxavir marboxil is catalyzed by [[Biology:AADAC|arylacetamide]] deacetylases in cells of the blood, liver, and lumen of the small intestine.<ref name= HughesOPRD2019>{{Cite journal|title=Review of the Patent Literature: Synthesis and Final Forms of Antiviral Drugs Tecovirimat and Baloxavir Marboxil| vauthors = Hughes DL |date=June 2019|journal=Organic Process Research & Development|volume=23|issue=7|pages=1298–1307|doi=10.1021/acs.oprd.9b00144|s2cid=197172102}}</ref><ref>{{cite journal | vauthors = Yoshino R, Yasuo N, Sekijima M | title = Molecular Dynamics Simulation reveals the mechanism by which the Influenza Cap-dependent Endonuclease acquires resistance against Baloxavir marboxil | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 17464 | date = November 2019 | pmid = 31767949 | doi = 10.1038/s41598-019-53945-1 | pmc = 6877583 | doi-access = free | title-link = doi | bibcode = 2019NatSR...917464Y }}</ref><ref>{{cite journal | vauthors = Kawaguchi N, Koshimichi H, Ishibashi T, Wajima T | title = Evaluation of Drug-Drug Interaction Potential between Baloxavir Marboxil and Oseltamivir in Healthy Subjects | journal = Clinical Drug Investigation | volume = 38 | issue = 11 | pages = 1053–1060 | date = November 2018 | pmid = 30203386 | doi = 10.1007/s40261-018-0697-2 | doi-access = free | title-link = doi }}</ref> The compound numbers for baloxavir marboxil and baloxavir acid used in publications by Shionogi and others during discovery and development (prior to assignment of a United States Adopted Name (USAN)) were, respectively, S-033188 and S-033447.<ref>{{cite journal | vauthors = Yang J, Huang Y, Liu S | title = Investigational antiviral therapies for the treatment of influenza | journal = Expert Opinion on Investigational Drugs | volume = 28 | issue = 5 | pages = 481–488 | date = May 2019 | pmid = 31018720 | doi = 10.1080/13543784.2019.1606210 | s2cid = 131775842 }}</ref> As reported in a review of the patent literature, the carbonic acid ester (carbonate) moiety of the prodrug—shown in the lower left-hand corner of the image above—was prepared during discovery and development research from a late stage 2-hydroxy-[[Chemistry:4-Pyridone|4-pyridone]] precursor by treatment with chloromethyl methyl carbonate.<ref name= HughesOPRD2019/><ref>{{Cite web|url=https://pharmaceutical-substances.thieme.com/ps/search-results?docUri=KD-02-0182|title=Baloxavir Marboxil|website=Pharmaceutical Substances|url-access=subscription|access-date=8 January 2020|archive-date=26 July 2020|archive-url=https://web.archive.org/web/20200726124827/https://pharmaceutical-substances.thieme.com/ps/search-results?docUri=KD-02-0182|url-status=live}}</ref>

== History ==
As of September 2018, in the only report of a Phase III randomized, controlled trial, baloxavir reduced the duration of influenza symptoms of otherwise healthy participants by about one day compared with a placebo treatment group, and comparable with what was seen for an [[Chemistry:Oseltamivir|oseltamivir]] treatment group.<ref name="FDA Snapshot" /> On the first day after baloxavir was started in its treatment group of participants, [[Biology:Viral load|viral load]]s decreased more than in participants in either the oseltamivir or placebo groups; however, after five days, the effect on viral load of the single dose of baloxavir was indistinguishable from the effect observed following the complete, 5-day regimen of oseltamivir in its treatment group.<ref name=nejm>{{cite journal |vauthors=Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, Ishida T, Sekino H, Yamada K, Portsmouth S, Kawaguchi K, Shishido T, Arai M, Tsuchiya K, Uehara T, Watanabe A |display-authors=6 |title=Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents |journal=N. Engl. J. Med. |volume=379 |issue=10 |pages=913–923 |date=September 2018 |pmid=30184455 |doi=10.1056/NEJMoa1716197|s2cid=52173453 | doi-access = free | title-link = doi }}</ref>{{verification needed|date=January 2020}}

Baloxavir marboxil was developed for the market by Shionogi Co., a {{wipe|Japan}}ese [[Chemistry:Pharmaceutical|pharmaceutical]] company, and {{wipe|Switzerland}}-based [[Company:Hoffmann-La Roche|Roche AG]].<ref name=stat>{{cite web |title=A flu drug — shown to reduce the duration of symptoms — could upend treatment in U.S. |url=https://www.statnews.com/2018/06/27/flu-drug-single-pill/ |website=Stat |date=27 June 2018 | vauthors = Branswell H |url-access=subscription |access-date=28 June 2018 |archive-date=20 October 2020 |archive-url=https://web.archive.org/web/20201020173446/https://www.statnews.com/2018/06/27/flu-drug-single-pill/ |url-status=live }}</ref> The names under which baloxavir marboxil and baloxavir acid appear in Shionogi research reporting are S-033188 and S-033447, respectively.{{cn|date=August 2022}}

== Society and culture ==
=== Legal status ===
Japan's [[Organization:Ministry of Health, Labour and Welfare|Ministry of Health, Labour and Welfare]] (JMHLW) and the US [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) approved baloxavir marboxil based on evidence of its benefits and side effects from two clinical trials in adult and pediatric participants with uncomplicated influenza (Trial 1, 1518T0821 and Trial 2, NCT02954354<ref>{{cite journal | title=A Study of S-033188 (Baloxavir Marboxil) Compared With Placebo or Oseltamivir in Otherwise Healthy Patients With Influenza | website=ClinicalTrials.gov | date=3 November 2016 | url=https://clinicaltrials.gov/ct2/show/NCT02954354 | access-date=11 August 2022 | archive-date=21 January 2022 | archive-url=https://web.archive.org/web/20220121063851/https://clinicaltrials.gov/ct2/show/NCT02954354 | url-status=live }}</ref>),<ref name="Xofluza FDA label" /> involving 1119 participants.<ref name="FDA Snapshot"/><ref>{{Cite news|url=https://www.japantimes.co.jp/news/2018/02/24/national/science-health/one-dose-flu-drug-xofluza-gets-nod-health-ministry/|title=One-dose flu drug Xofluza gets nod from health ministry| vauthors = Otake T |date=24 February 2018|newspaper=Japan Times Online|access-date=8 January 2020|archive-date=2 November 2021|archive-url=https://web.archive.org/web/20211102132324/https://www.japantimes.co.jp/news/2018/02/24/national/science-health/one-dose-flu-drug-xofluza-gets-nod-health-ministry/|url-status=live}}</ref>{{better source needed|date=January 2020}}{{verification needed|date=January 2020}} Both trials included clinical sites and participants in Japan, with Trial 2 adding clinical locations in the United States.<ref name="Xofluza FDA label" /><ref name="FDA Snapshot" />

Baloxavir marboxil was approved for sale in Japan in February 2018.<ref>{{cite press release|url=http://www.publicnow.com/view/7E9FBF87835EEBAC31508CC4E1F96D3D77D54C0A|title=Xofluza (Baloxavir Marboxil) Tablets 10mg/20mg Approved For The Treatment Of Influenza Types A And B In Japan|date=23 February 2018|via=publicnow.com|publisher=Shionogi & Co., Ltd.|access-date=23 February 2018|archive-date=20 January 2021|archive-url=https://web.archive.org/web/20210120045007/http://www.publicnow.com/view/7E9FBF87835EEBAC31508CC4E1F96D3D77D54C0A|url-status=live}}</ref>{{better source needed|date=January 2020}} In October 2018, the FDA approved it for the treatment of acute uncomplicated influenza in people twelve years of age and older who have been symptomatic for no more than 48 hours.<ref name="FDA PR 20181024"/><ref name="FDA approval 2018">{{cite web | title=Drug Approval Package: Xofluza Film-Coated Tablets (Baloxavir marboxil) | publisher=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | date=7 December 2018 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210854Orig1s000TOC.cfm | access-date=10 May 2020 | archive-date=26 July 2020 | archive-url=https://web.archive.org/web/20200726125547/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210854Orig1s000TOC.cfm | url-status=live }} {{PD-notice}}</ref> The FDA application of baloxavir marboxil was granted [[Medicine:Priority review|priority review]] in the United States, and approval of Xofluza was granted to Shionogi & Co., Ltd. in October 2018.<ref name="FDA PR 20181024"/><ref name="FDA approval 2018" /> Specifically, the FDA approved the use of baloxavir marboxil for people at high risk of developing influenza-related complications.<ref>{{cite press release | title=Genentech Announces FDA Approval of Xofluza (Baloxavir Marboxil) for People at High Risk of Developing Influenza-Related Complications | publisher=[[Company:Genentech|Genentech]] | via=Business Wire | date=17 October 2019 | url=https://www.businesswire.com/news/home/20191017005525/en | archive-url=https://web.archive.org/web/20191024061608/https://www.businesswire.com/news/home/20191017005525/en | archive-date=24 October 2019 | url-status=live | access-date=23 October 2019}}</ref> In October 2019, the FDA approved an updated [[Medicine:Indication|indication]] for the treatment of acute, uncomplicated influenza in people twelve years of age and older at risk of influenza complications.<ref name="FDA approval 2019">{{cite web | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/210854Orig1s001.pdf | title=FDA Approval Package for 210854Orig1s001 | publisher=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | date=16 October 2019 | access-date=30 September 2020 | archive-date=9 April 2021 | archive-url=https://web.archive.org/web/20210409102411/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/210854Orig1s001.pdf | url-status=live }} {{PD-notice}}</ref> In November 2020, the FDA approved an updated indication to include post-exposure prevention of influenza (flu) for people twelve years of age and older after contact with an individual who has the flu.<ref name="FDA PR 20201123">{{cite press release | title=FDA Expands Approval of Influenza Treatment to Post-Exposure Prevention | publisher=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | date=23 November 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-expands-approval-influenza-treatment-post-exposure-prevention | access-date=23 November 2020 | archive-date=23 November 2020 | archive-url=https://web.archive.org/web/20201123181242/https://www.fda.gov/news-events/press-announcements/fda-expands-approval-influenza-treatment-post-exposure-prevention | url-status=live }} {{PD-notice}}</ref>

Baloxavir marboxil was approved for medical use in Australia in February 2020.<ref name="Xofluza APMDS" />

The safety and efficacy of baloxavir marboxil, an antiviral drug taken as a single oral dose, was demonstrated in two randomized controlled clinical trials of 1,832 subjects where participants were assigned to receive either baloxavir marboxil, a placebo, or another antiviral flu treatment within 48 hours of experiencing flu symptoms.<ref name="FDA PR 20181024" /> In both trials, subjects treated with baloxavir marboxil had a shorter time to alleviation of symptoms compared with subjects who took the placebo.<ref name="FDA PR 20181024" /> In the second trial, there was no difference in the time to alleviation of symptoms between subjects who received baloxavir marboxil and those who received the other flu treatment.<ref name="FDA PR 20181024" />

The safety and efficacy of baloxavir marboxil for post-flu exposure prevention is supported by one randomized, double-blind, controlled trial in which 607 subjects, twelve years of age and older who were exposed to a person with influenza in their household, received either a single dose of baloxavir marboxil or a single dose of a placebo.<ref name="FDA PR 20201123" /> Of these 607 subjects, 303 received baloxavir marboxil and 304 received the placebo.<ref name="FDA PR 20201123" /> The trial's primary endpoint was the proportion of subjects who were infected with influenza virus and presented with fever and at least one respiratory symptom from day 1 to day 10.<ref name="FDA PR 20201123" /> Of those who received baloxavir marboxil, 1% of subjects met these criteria, compared to 13% of subjects who received a placebo for the clinical trial.<ref name="FDA PR 20201123" />

Baloxavir marboxil was approved for medical use in the European Union in January 2021.<ref name="Xofluza EPAR">{{cite web | title=Xofluza EPAR | website=[[Organization:European Medicines Agency|European Medicines Agency]] (EMA) | date=9 November 2020 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/xofluza | access-date=25 January 2021 | archive-date=30 January 2021 | archive-url=https://web.archive.org/web/20210130161313/https://www.ema.europa.eu/en/medicines/human/EPAR/xofluza | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>

==References==
{{reflist}}

==Further reading==
* {{cite journal |vauthors=Ikematsu H, Hayden FG, Kawaguchi K, Kinoshita M, de Jong MD, Lee N, Takashima S, Noshi T, Tsuchiya K, Uehara T | display-authors=6 |title=Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts |journal=N. Engl. J. Med. |volume=383 |issue=4 |pages=309–320 |date=July 2020 |pmid=32640124 |doi=10.1056/NEJMoa1915341 | doi-access = free | title-link = doi }}
* {{cite journal | vauthors = Mushtaq A | date = December 2018 | title = Baloxavir: game-changer or much ado about nothing? | journal = Lancet Respir Med | volume = 6 | issue = 12 | pages = 903–904 | doi = 10.1016/S2213-2600(18)30469-7 | pmid=30420246 | doi-access = free | title-link = doi }}

== External links ==
* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/baloxavir%20marboxil | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Baloxavir marboxil }}
* {{cite web | title=Baloxavir marboxil | website=SPS - Specialist Pharmacy Service | date=29 June 2018 | url=https://www.sps.nhs.uk/medicines/baloxavir-marboxil/ | access-date=10 May 2020 | archive-date=26 July 2020 | archive-url=https://web.archive.org/web/20200726131836/https://www.sps.nhs.uk/medicines/baloxavir-marboxil/ | url-status=dead }}

{{Influenza}}

[[Category:Carbonate esters]]
[[Category:Fluoroarenes]]
[[Category:Nitrogen heterocycles]]
[[Category:Morpholines]]
[[Category:Prodrugs]]
[[Category:Sulfur heterocycles]]
[[Category:4-Pyridones]]
[[Category:Orphan drugs]]

{{Sourceattribution|Baloxavir marboxil}}