Atovaquone/proguanil

Atovaquone/proguanil, sold under the trade names Malarone among others, is a combination of two antimalarial medication atovaquone and proguanil.[2] It is used to treat and prevent malaria, including chloroquine-resistant malaria.[3][2] It is not recommended for severe or complicated malaria.[2] It is taken by mouth.[2]

Atovaquone/proguanil
Combination of
AtovaquoneAntimalarial medication
ProguanilAntimalarial medication
Clinical data
Trade namesMalarone, Malanil, others
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
  • In general: ℞ (Prescription only)
Identifiers
PubChem CID
ChemSpider
KEGG
 NY (what is this?)  (verify)

Common side effects include abdominal pain, vomiting, diarrhea, cough, and itchiness.[2] Serious side effects may include anaphylaxis, Stevens-Johnson syndrome, hallucinations, and liver problems.[2][4] It is unclear if use during pregnancy or breastfeeding is safe for the baby.[5] It is not recommended to prevent malaria in those with poor kidney function.[4] Atovaquone works by interfering with the function of mitochondria in malaria while proguanil by blocking dihydrofolate reductase.[2]

Atovaquone/proguanil was approved for medical use in the United States in 2000.[2] It has been available as a generic medication since 2011.[6] In the United Kingdom it costs £2.10 per dose as of 2019.[4] The wholesale cost in the United States is $US 2.82 per dose as of 2019.[7]

Medical use
Malarone tablets, as issued in the UK.

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 kg: 1 standard tablet once daily for 3 days;
  • 21 to 30 kg: 2 standard tablets once daily for 3 days;
  • 31 to 40 kg: 3 standard tablets once daily for 3 days;
  • 41 kg and above: use adult dose.

Atovaquone/proguanil is not licensed for use in children weighing 10 kg or less. The pediatric tablets are not used in malaria treatment, but are used for prophylaxis.

Atovaquone/proguanil is not normally used to treat severe malaria, when an injectable drug such as quinine is used instead.

Prevention

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. Also, stomach irritation may occur if one lies down within a half hour after taking this medicine.

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 seven days after returning from the area.

The child dose is prescribed according to body weight:

  • 11–20 kg: 1 pediatric tablet once daily;
  • 21–30 kg: 2 pediatric tablets once daily;
  • 31–40 kg: 3 pediatric tablets once daily;
  • 41 kg and above use adult dose.

The duration of treatment is the same as for adults.

Resistance

Proguanil acts as a mitochondrial sensitiser and synergizes with atovaquone. When atovaquone is used as a sole agent, a high natural frequency of cytochrome b 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.[8] Specific mutations (Y268S, Y268C) have been shown to confer resistance in vivo,[9][10][11] but the other mechanisms of resistance remain unknown.[12]

Adverse effects

Side effects are generally mild.[13] 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.[13]

Mechanism of action

Atovaquone selectively inhibits the malarial cytochrome bc1 complex in the parasitic electron transport chain, collapsing the mitochondrial membrane potential.[14] 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.[15]

Proguanil, via its metabolite cycloguanil, functions as a dihydrofolate reductase inhibitor, halting parasitic deoxythymidilate synthesis.[16]

Chemistry

A standard tablet of Malarone contains 100 mg of proguanil hydrochloride and 250 mg of atovaquone. A pediatric tablet contains 25 mg of proguanil hydrochloride and 62.5 mg of atovaquone.

History

Glaxo Wellcome patented the combination of atovaquone and proguanil to treat malaria in 1999. Patent protection expired in 2013.[17] The U.S. Food and Drug Administration (FDA) approved a generic formulation from Glenmark Generics in 2011.[18] In February 2013, the United Kingdom High Court revoked Glaxo's patent on grounds of obviousness, which clears the way for firms to sell generic versions there.[19]

References
  1. Glaxo Smith Kline monograph on MALARONE
  2. "Atovaquone and Proguanil Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 12 September 2019.
  3. Nakato, Halima; Vivancos, Roberto; Hunter, Paul R. (2007-11-01). "A systematic review and meta-analysis of the effectiveness and safety of atovaquone–proguanil (Malarone) for chemoprophylaxis against malaria". Journal of Antimicrobial Chemotherapy. 60 (5): 929–936. doi:10.1093/jac/dkm337. ISSN 0305-7453. PMID 17848375.
  4. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 604. ISBN 9780857113382.
  5. "Atovaquone / proguanil Use During Pregnancy". Drugs.com. Retrieved 12 September 2019.
  6. "Generic Malarone Availability". Drugs.com. Retrieved 12 September 2019.
  7. "NADAC as of 2019-09-11 | Data.Medicaid.gov". Centers for Medicare and Medicaid Services. Retrieved 12 September 2019.
  8. Srivastava, Indresh K.; Vaidya, Akhil B. (1999-06-01). "A Mechanism for the Synergistic Antimalarial Action of Atovaquone and Proguanil". Antimicrobial Agents and Chemotherapy. 43 (6): 1334–1339. doi:10.1128/AAC.43.6.1334. ISSN 0066-4804. PMC 89274. PMID 10348748.
  9. Färnet A, Lindberg J, Gil P, et al. (2003). "Evidence of Plasmodium falciparum malaria resistant to atovaquone and proguoanil hydrochloride: case reports". Br Med J. 326 (7390): 628–29. doi:10.1136/bmj.326.7390.628. PMC 151974. PMID 12649236.
  10. Fivelman QL, Butcher GA, Adagu IS, et al. (2002). "Malarone treatment failure and in-vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos, Nigeria". Malaria Journal. 1: 1. doi:10.1186/1475-2875-1-1. PMC 111499. PMID 12057021.
  11. Schwartz E, Bujanover S, Kain KC (2003). "Genetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveller to east Africa". Clin Infect Dis. 37 (3): 450–51. doi:10.1086/375599. PMID 12884171.
  12. Wichmann O, Muehlen M, Gruss H, et al. (2004). "Malarone treatment failure not associated with previously described mutations in the cytochrome b gene". Malaria Journal. 3: 14. doi:10.1186/1475-2875-3-14. PMC 425592. PMID 15186499.
  13. "Malarone Side Effects: Common, Severe, Long Term". Drugs.com. Retrieved 12 September 2019.
  14. Fry, Mitchell; Pudney, Mary (1992-04-01). "Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4'-chlorophenyl) cyclohexyl]-3- hydroxy-1,4-naphthoquinone (566C80)". Biochemical Pharmacology. 43 (7): 1545–1553. doi:10.1016/0006-2952(92)90213-3. PMID 1314606.
  15. Srivastava, Indresh K.; Rottenberg, Hagai; Vaidya, Akhil B. (1997-02-14). "Atovaquone, a Broad Spectrum Antiparasitic Drug, Collapses Mitochondrial Membrane Potential in a Malarial Parasite". Journal of Biological Chemistry. 272 (7): 3961–3966. doi:10.1074/jbc.272.7.3961. ISSN 0021-9258. PMID 9020100.
  16. http://us.gsk.com/products/assets/us_malarone.pdf
  17. Generic Malarone Availability
  18. Drug Details
  19. Atovaquone Proguanil (Malarone) Patent Revoked & Glenmark Launches First UK Generic
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