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Revision as of 09:49, 3 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'StdInChI', 'StdInChIKey', 'KEGG').← Previous edit Latest revision as of 20:52, 14 September 2024 edit undoRuslik0 (talk | contribs)Edit filter managers, Administrators54,752 editsm Reverted edit by Hitenbhai (talk) to last version by 37.47.72.199Tag: Rollback 
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{{Short description|Chemical compound}}
{{Use dmy dates|date=April 2023}}
{{Drugbox {{Drugbox
| Verifiedfields = changed
| verifiedrevid = 458781507
⚫ | type = combo


<!--Combo data--> <!--Combo data-->
⚫ | type = combo
| component1 = Atovaquone | component1 = Atovaquone
| class1 = ] | class1 = ]
Line 9: Line 13:


<!--Clinical data--> <!--Clinical data-->
| tradename = | tradename = Malarone, Malanil, others
| Drugs.com = {{drugs.com|monograph|atovaquone-and-proguanil-hydrochloride}} | Drugs.com = {{drugs.com|monograph|atovaquone-and-proguanil-hydrochloride}}
| licence_EU = <!-- EMEA requires brand name --> | licence_EU = <!-- EMEA requires brand name -->
| DailyMedID = Atovaquone_and_proguanil
| licence_US = Malarone
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU = B2<!-- A / B1 / B2 / B3 / C / D / X -->
⚫ | routes_of_administration = ]
| pregnancy_US =
⚫ | ATC_prefix = P01
| pregnancy_category =
⚫ | ATC_suffix = BB51
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| ATC_supplemental =

| legal_AU = S4
| legal_AU_comment = <ref>{{cite web | title=Atovaquopro Lupin (Generic Health Pty Ltd) | website=Therapeutic Goods Administration (TGA) | date=28 September 2022 | url=https://www.tga.gov.au/resources/prescription-medicines-registrations/atovaquopro-lupin-generic-health-pty-ltd | access-date=29 April 2023 |archive-date=12 October 2022 |archive-url=https://web.archive.org/web/20221012060341/https://www.tga.gov.au/resources/prescription-medicines-registrations/atovaquopro-lupin-generic-health-pty-ltd |url-status=live }}</ref>
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = POM | legal_UK = POM
| legal_US = | legal_US = Rx-only
| legal_status = Rx | legal_status = Rx-only
| dependency_liability =
⚫ | routes_of_administration = ]


<!--Identifiers--> <!--Identifiers-->
| CAS_number = 156879-69-5
⚫ | ATC_prefix = P01
⚫ | ATC_suffix = BB51
| StdInChI = 1S/C22H19ClO3.C11H16ClN5.ClH/c23-16-11-9-14(10-12-16)13-5-7-15(8-6-13)19-20(24)17-3-1-2-4-18(17)21(25)22(19)26;1-7(2)15-10(13)17-11(14)16-9-5-3-8(12)4-6-9;/h1-4,9-13,15,26H,5-8H2;3-7H,1-2H3,(H5,13,14,15,16,17);1H/t13-,15-;;
| StdInChIKey = VLGMAGFZQDMEGN-BKRMEZGBSA-N
| PubChem = 11954242 | PubChem = 11954242
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 21230364 | ChemSpiderID = 21230364
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = <!-- blanked - oldvalue: D02472 -->
| KEGG = D02472
<!--Chemical data-->
}} }}
<!-- Definition and medical uses -->
⚫ ]
'''Atovaquone/proguanil''', sold under the brand name '''Malarone''' among others, is a ] medication used to treat and prevent ], including ]-resistant malaria.<ref>{{cite journal | vauthors = Nakato H, Vivancos R, Hunter PR | title = A systematic review and meta-analysis of the effectiveness and safety of atovaquone proguanil (Malarone) for chemoprophylaxis against malaria | journal = The Journal of Antimicrobial Chemotherapy | volume = 60 | issue = 5 | pages = 929–936 | date = November 2007 | pmid = 17848375 | doi = 10.1093/jac/dkm337 | doi-access = free }}</ref><ref name=AHSF2019>{{cite web |title=Atovaquone and Proguanil Hydrochloride Monograph for Professionals |url=https://www.drugs.com/monograph/atovaquone-and-proguanil-hydrochloride.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=12 September 2019 |language=en |archive-date=20 December 2016 |archive-url=https://web.archive.org/web/20161220223925/https://www.drugs.com/monograph/atovaquone-and-proguanil-hydrochloride.html |url-status=live }}</ref> It contains ] and ].<ref name=AHSF2019/> It is not recommended for severe or complicated malaria.<ref name=AHSF2019/> It is taken by mouth.<ref name=AHSF2019/>


<!-- Side effects and mechanism -->
The ] combination ''']/]''' (], trade name '''Malarone''') is an ] used in both the treatment and prevention of ], commercially available from ] since 2000. Atovaquone alone is not indicated for treatment or prevention of malaria as ] (i.e. without proguanil).
Common side effects include abdominal pain, vomiting, diarrhea, cough, and itchiness.<ref name=AHSF2019/> Serious side effects may include ], ], ], and liver problems.<ref name=AHSF2019/><ref name=BNF76>{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=604|edition=76}}</ref> Side effects are generally mild.<ref name=Drug2019Side/> It is unclear if use during pregnancy or breastfeeding is safe for the baby.<ref>{{cite web |title=Atovaquone / proguanil Use During Pregnancy |url=https://www.drugs.com/pregnancy/atovaquone-proguanil.html |website=Drugs.com |access-date=12 September 2019 |language=en |archive-date=16 August 2019 |archive-url=https://web.archive.org/web/20190816072546/https://www.drugs.com/pregnancy/atovaquone-proguanil.html |url-status=live }}</ref> It is not recommended to prevent malaria in those with poor kidney function.<ref name=BNF76/> Atovaquone works by interfering with the function of ] in malaria while proguanil blocks ].<ref name=AHSF2019/>


<!-- History and culture -->
⚫ A "standard" tablet of Malarone contains 100&nbsp;mg of proguanil hydrochloride and 250&nbsp;mg of atovaquone. A "pediatric" tablet of Malarone contains 25&nbsp;mg of proguanil hydrochloride and 62.5&nbsp;mg of atovaquone.
Atovaquone/proguanil was approved for medical use in the United States in 2000.<ref name=AHSF2019/> It has been available as a ] since 2011.<ref>{{cite web |title=Generic Malarone Availability |url=https://www.drugs.com/availability/generic-malarone.html |website=Drugs.com |access-date=12 September 2019 |language=en |archive-date=16 August 2019 |archive-url=https://web.archive.org/web/20190816072535/https://www.drugs.com/availability/generic-malarone.html |url-status=live }}</ref>


==Medical use== ==Medical uses==
⚫ ]
===Treatment===
The adult treatment dose is four "standard" tablets once a day for three days. In children, the drug is prescribed by body weight:
*11 to 20&nbsp;kg: 1 "standard" tablet once daily for 3 days;
*21 to 30&nbsp;kg: 2 "standard" tablets once daily for 3 days;
*31 to 40&nbsp;kg: 3 "standard" tablets once daily for 3 days;
*41&nbsp;kg and above: use adult dose.


===Malaria treatment===
Malarone is not licensed for use in children weighing 10&nbsp;kg or less. The "pediatric" tablets are ''not'' used in malaria treatment.
Atovaquone/proguanil is not normally used to treat severe malaria, when an injectable drug such as ] is used instead.{{cn|date=December 2022}}


===Malaria prevention===
The advice of a specialist should always be sought when starting malaria treatment. Malarone should not be used to treat severe malaria, when an injectable drug (] or ] in the UK; ] in the US) should be used instead.
Since some malaria strains are resistant to atovaquone/proguanil, it is not effective in all parts of the world. It must be taken with a fatty meal, or at least some milk, for the body to absorb it adequately—and to avoid painful stomach irritation, which proguanil frequently causes if taken without food. {{cn|date=December 2022}}


===Prevention=== ===Resistance===
⚫ Proguanil acts as a ] sensitiser and synergizes with atovaquone. When atovaquone is used as a sole agent, a high natural frequency of ] mutants leads to a high failure rate. This is potentially due to the high lipophilicity and slow uptake of atovaquone, which results in a relatively prolonged period of parasite exposure at ineffective concentrations.<ref>{{cite journal | vauthors = Srivastava IK, Vaidya AB | title = A mechanism for the synergistic antimalarial action of atovaquone and proguanil | journal = Antimicrobial Agents and Chemotherapy | volume = 43 | issue = 6 | pages = 1334–1339 | date = June 1999 | pmid = 10348748 | pmc = 89274 | doi = 10.1128/AAC.43.6.1334 }}</ref> Specific mutations (''Y268S'', ''Y268C'') have been shown to confer resistance ''in vivo'',<ref>{{cite journal | vauthors = Färnert A, Lindberg J, Gil P, Swedberg G, Berqvist Y, Thapar MM, Lindegårdh N, Berezcky S, Björkman A | display-authors = 6 | title = Evidence of Plasmodium falciparum malaria resistant to atovaquone and proguanil hydrochloride: case reports | journal = BMJ | volume = 326 | issue = 7390 | pages = 628–629 | date = March 2003 | pmid = 12649236 | pmc = 151974 | doi = 10.1136/bmj.326.7390.628 }}</ref><ref>{{cite journal | vauthors = Fivelman QL, Butcher GA, Adagu IS, Warhurst DC, Pasvol G | title = Malarone treatment failure and in vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos, Nigeria | journal = Malaria Journal | volume = 1 | pages = 1 | date = February 2002 | pmid = 12057021 | pmc = 111499 | doi = 10.1186/1475-2875-1-1 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Schwartz E, Bujanover S, Kain KC | title = Genetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa | journal = Clinical Infectious Diseases | volume = 37 | issue = 3 | pages = 450–451 | date = August 2003 | pmid = 12884171 | doi = 10.1086/375599 | doi-access = free }}</ref> but the other mechanisms of resistance remain unknown.<ref>{{cite journal | vauthors = Wichmann O, Muehlen M, Gruss H, Mockenhaupt FP, Suttorp N, Jelinek T | title = Malarone treatment failure not associated with previously described mutations in the cytochrome b gene | journal = Malaria Journal | volume = 3 | pages = 14 | date = June 2004 | pmid = 15186499 | pmc = 425592 | doi = 10.1186/1475-2875-3-14 | doi-access = free }}</ref>
Medical advice should always be taken before choosing a drug for malaria prevention. Because some strains of malaria are resistant, Malarone is not effective for malaria prevention in all parts of the world. It must be taken with a fatty meal or at least some milk to be absorbed adequately.

The adult dose is one "standard" tablet daily starting one or two days before traveling into a malaria-endemic area, and continuing throughout the stay and then for another 7 days after returning from the malarious area.

The child dose is prescribed according to body weight:
*11&ndash;20&nbsp;kg: 1 "pediatric" tablet once daily;
*21&ndash;30&nbsp;kg: 2 "pediatric" tablets once daily;
*31&ndash;40&nbsp;kg: 3 "pediatric" tablets once daily;
*41&nbsp;kg and above use adult dose.
The duration of treatment is the same as for adults.

==Resistance==
⚫ Proguanil acts as a ] sensitiser and synergizes with atovaquone; also, there is a high natural frequency of ] mutants which leads to a high failure rate if atovaquone is used on its own to treat malaria. Specific mutations (Y268S, Y268C) have been shown to confer resistance ''in vivo,''<ref>{{cite journal | author=Färnet A, Lindberg J, Gil P, ''et al.'' | title=Evidence of ''Plasmodium falciparum'' malaria resistant to atovaquone and proguoanil hydrochloride: case reports | year=2003 | journal=Brit Med J | volume=326 | pages=628&ndash;29 | doi=10.1136/bmj.326.7390.628 | pmid=12649236 | issue=7390 | pmc=151974 }}</ref><ref>{{cite journal | author=Fivelman QL, Butcher GA, Adagu IS, ''et al.'' | title=Malarone treatment failure and in-vitro confirmation of resistance of ''Plasmodium falciparum'' isolate from Lagos, Nigeria | year=2002 | journal=Malaria J | volume=1 | pages=1 | doi=10.1186/1475-2875-1-1 }}</ref><ref>{{cite journal | author=Schwartz E, Bujanover S, Kain KC | title=Genetic confirmation of atovaquone-proguanil-resistant ''Plasmodium falciparum'' malaria acquired by a nonimmune traveller to east Africa | year=2003 | journal=Clin Infect Dis | volume=37 | pages=450&ndash;51 | doi=10.1086/375599 | pmid=12884171 | issue=3 }}</ref> but there are other mechanisms of resistance that remain unknown.<ref>{{cite journal | author=Wichmann O, Muehlen M, Gruss H, ''et al.'' | title=Malarone treatment failure not associated with previously described mutations in the cytochrome b gene | year=2004 | journal=Malaria J | volume=3 | pages=14 | doi=10.1186/1475-2875-3-14 | pmid=15186499 | pmc=425592 }}</ref>


==Adverse effects== ==Adverse effects==
Side effects are generally mild.<ref name=Drug2019Side/> While some people experience side effects, such as coughing, diarrhea, dizziness, headache, loss of appetite, mouth sores, nausea, stomach pain, vomiting, or weakness, the majority have none or few of these.<ref name=Drug2019Side>{{cite web |title=Malarone Side Effects: Common, Severe, Long Term |url=https://www.drugs.com/sfx/malarone-side-effects.html |website=Drugs.com |access-date=12 September 2019 |language=en |archive-date=16 August 2019 |archive-url=https://web.archive.org/web/20190816072534/https://www.drugs.com/sfx/malarone-side-effects.html |url-status=live }}</ref>
Some people have difficulty sleeping (nightmares, incoherent dreams) while taking Malarone. Headaches and stomach irritation have also been reported, though this can be helped by taking the drug with food or a milky drink. Muscle fatigue and hard stools have also been reported.


==Mechanism of action== ==Mechanism of action==
Atovaquone selectively inhibits the malarial cytochrome ''bc''<sub>1</sub> complex in the parasitic ], collapsing the mitochondrial membrane potential.<ref>{{cite journal | vauthors = Fry M, Pudney M | title = Site of action of the antimalarial hydroxynaphthoquinone, 2--3-hydroxy-1,4-naphthoquinone (566C80) | journal = Biochemical Pharmacology | volume = 43 | issue = 7 | pages = 1545–1553 | date = April 1992 | pmid = 1314606 | doi = 10.1016/0006-2952(92)90213-3 }}</ref> The malarial electron transport chain does not contribute significantly to ATP synthesis; thus, it is believed that parasite death is due to the indirect inhibition of dihydroorotate dehydrogenase, which requires transport chain function and is essential to pyrimidine biosynthesis.<ref>{{cite journal | vauthors = Srivastava IK, Rottenberg H, Vaidya AB | title = Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite | journal = The Journal of Biological Chemistry | volume = 272 | issue = 7 | pages = 3961–3966 | date = February 1997 | pmid = 9020100 | doi = 10.1074/jbc.272.7.3961 | doi-access = free }}</ref>
Atovaquone selectively inhibits the parasitic ].


Proguanil, via its metabolite ], functions as a ], halting parasitic ] synthesis.<ref>http://us.gsk.com/products/assets/us_malarone.pdf</ref> Proguanil, via its metabolite ], functions as a ], halting parasitic ] synthesis.<ref>{{Cite web|url=http://us.gsk.com/products/assets/us_malarone.pdf|title=Our prescription medicines &#124; GSK US|access-date=28 September 2011|archive-date=4 September 2011|archive-url=https://web.archive.org/web/20110904232305/http://us.gsk.com/products/assets/us_malarone.pdf|url-status=dead}}</ref>


==References== ===Chemistry===
⚫ A standard tablet of Malarone contains 100&nbsp;mg of proguanil hydrochloride and 250&nbsp;mg of atovaquone. A pediatric tablet contains 25&nbsp;mg of proguanil hydrochloride and 62.5&nbsp;mg of atovaquone.{{cn|date=December 2022}}

==History==
] patented the combination of atovaquone and proguanil to treat malaria in 1999. Patent protection expired in 2013.<ref name="generic">{{Cite web |url=https://www.drugs.com/availability/generic-malarone.html |title=Generic Malarone Availability |access-date=23 January 2018 |archive-date=16 August 2019 |archive-url=https://web.archive.org/web/20190816072535/https://www.drugs.com/availability/generic-malarone.html |url-status=live }}</ref> The U.S. ] (FDA) approved a generic formulation from ] in 2011.<ref name="fda_generic">{{Cite web |url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=091211&DrugName=ATOVAQUONE%20AND%20PROGUANIL%20HYDROCHLORIDE&ActiveIngred=ATOVAQUONE%3B%20PROGUANIL%20HYDROCHLORIDE&SponsorApplicant=GLENMARK%20GENERICS&ProductMktStatus=1&goto=Search.DrugDetails |title=Drug Details |access-date=1 May 2013 |archive-date=27 August 2021 |archive-url=https://web.archive.org/web/20210827232613/https://www.accessdata.fda.gov/scripts/cder/daf/ |url-status=live }}</ref> In February 2013, the ] High Court revoked Glaxo's patent on grounds of obviousness, which clears the way for firms to sell generic versions there.<ref name="uk">{{Cite web |url=http://www.prnewswire.co.uk/news-releases/atovaquone-proguanil-malarone-patent-revoked--glenmark-launches-first-uk-generic-190203571.html |title=Atovaquone Proguanil (Malarone) Patent Revoked & Glenmark Launches First UK Generic |access-date=1 May 2013 |archive-date=16 April 2013 |archive-url=https://web.archive.org/web/20130416001054/http://www.prnewswire.co.uk/news-releases/atovaquone-proguanil-malarone-patent-revoked--glenmark-launches-first-uk-generic-190203571.html |url-status=live }}</ref>

== References ==
{{Reflist}} {{Reflist}}


{{Antimalarials|state=collapsed}}
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{{GlaxoSmithKline}}
{{Portal bar | Medicine}}

{{DEFAULTSORT:Atovaquone Proguanil}}
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