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Atovaquone and Proguanil Hydrochloride

Class: Antimalarials
Chemical Name: trans-2-[4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione
CAS Number: 95233-18-4
Brands: Malarone

Introduction

Antimalarial; fixed combination containing atovaquone (hydroxynaphthoquinone derivative) and proguanil (biguanide derivative).1 161

Uses for Atovaquone and Proguanil Hydrochloride

Prevention of Malaria

Prevention (prophylaxis) of malaria caused by Plasmodium falciparum (including chloroquine-resistant P. falciparum).1 5 6 9 10 115 121 134

Recommended by CDC and others as a drug of choice for prophylaxis in those traveling to areas where chloroquine-resistant P. falciparum malaria has been reported;115 121 134 also can be used for prophylaxis in those traveling to areas where chloroquine-resistant P. falciparum has not been reported.115 121 134

Risk of acquiring malaria varies substantially from traveler to traveler and from region to region (even within a single country) because of differences in intensity of malaria transmission within the various regions and season, itinerary, duration, and type of travel.115 121 Malaria transmission occurs in large areas of Africa, Central and South America, parts of the Caribbean, Asia (including South Asia, Southeast Asia, and the Middle East), Eastern Europe, and the South Pacific.115 Mosquito avoidance measures must be used in conjunction with prophylaxis since no drug is 100% effective in preventing malaria.121

Choice of antimalarial for prophylaxis depends on traveler’s risk of acquiring malaria in area(s) visited, risk of exposure to drug-resistant P. falciparum, other medical conditions (e.g., pregnancy), cost, and potential adverse effects.115 121 134

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Active only against asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages) and cannot prevent delayed primary attacks or relapse of P. ovale or P. vivax malaria or provide a radical cure;115 134 terminal prophylaxis with 14-day regimen of primaquine may be indicated in addition to mefloquine prophylaxis if travelers were exposed in areas where P. ovale or P. vivax is endemic.115 134

Information on risk of malaria in specific countries and mosquito avoidance measures and recommendations regarding whether prevention of malaria indicated and choice of antimalarials for prevention are available from CDC at and .115

Presumptive Self-treatment of Malaria

Presumptive self-treatment of malaria in travelers.115 134

In consultation with their health-care provider, some travelers (e.g., those who elect not to use prophylaxis, those who use a prophylaxis regimen that may not have optimal efficacy, those who use effective prophylaxis but will be in very remote areas) may elect to take along an appropriate antimalarial to use for presumptive self-treatment if necessary.115 134

Self-treatment in these situations should be initiated promptly in the event of an influenza-like illness (e.g., fever, chills) if professional medical carenot readily available.115 134

CDC and other experts recommend fixed combination of atovaquone and proguanil (atovaquone/proguanil) or fixed combination of artemether and lumefantrine (artemether/lumefantrine) for presumptive self-treatment of malaria.115 134

Presumptive self-treatment of possible malarial infection is a temporary measure; it is imperative that a professional medical evaluation be obtained as soon as possible.115

Treatment of Uncomplicated Malaria

Treatment of acute, uncomplicated malaria caused by P. falciparum (including chloroquine-resistant P. falciparum)1 7 8 13 14 134 143 or chloroquine-resistant P. vivax.143

For treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum or treatment of uncomplicated malaria when plasmodial species not identified, CDC recommends atovaquone/proguanil, artemether/lumefantrine, or regimen of quinine in conjunction with doxycycline, tetracycline, or clindamycin.143 144

For treatment of uncomplicated malaria caused by chloroquine-susceptible P. falciparum, P. malariae, or P. knowlesi or treatment of uncomplicated malaria when plasmodial species not identified and infection acquired in areas where chloroquine resistance not reported, CDC recommends chloroquine (or hydroxychloroquine).143 144 Alternatively, CDC states that any of the regimens recommended for treatment of uncomplicated chloroquine-resistant P. falciparum malaria may be used if preferred, more readily available, or more convenient.143 144

For treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax, CDC recommends regimen of quinine and doxycycline (or tetracycline) given in conjunction with primaquine, atovaquone/proguanil given in conjunction with primaquine, or mefloquine given in conjunction with primaquine.143 144

Pediatric patients with uncomplicated malaria generally can receive same treatment regimens recommended for adults using age- and weight-appropriate drugs and dosages.143 144 For treatment of uncomplicated chloroquine-resistant P. falciparum in children <8 years of age, atovaquone/proguanil or artemether/lumefantrine usually recommended, but mefloquine can be considered if no other options available.144 For treatment of chloroquine-resistant P. vivax malaria in children <8 years of age, CDC recommends mefloquine given in conjunction with primaquine.143 144 Alternatively, if mefloquine not available or not tolerated and if potential benefits outweigh risks, atovaquone/proguanil or artemether/lumefantrine can be used for treatment of chloroquine-resistant P. vivax in this age group.143 144

Because atovaquone/proguanil active only against asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages), 14-day regimen of primaquine indicated to eradicate hypnozoites and prevent delayed primary attacks or relapse and provide a radical cure whenever atovaquone/proguanil used for treatment of P. ovale or P. vivax malaria.134 143 144

Not indicated for treatment of severe or complicated malaria.1

Assistance with diagnosis or treatment of malaria is available from CDC Malaria Hotline at 770-488-7788 or 855-856-4713 from 9:00 a.m. to 5:00 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.143 144

Atovaquone and Proguanil Hydrochloride Dosage and Administration

Administration

Oral Administration

Administer orally with food or milky drink.1

Usually once daily as a single dose, given at same time each day.1

If vomiting occurs within 1 hour of taking a dose, repeat the dose.1 Antiemetic agents may be used if necessary.1 (See Drug Interactions: Metoclopramide.)

For children who have difficulty swallowing tablets, the tablets may be crushed and mixed with condensed milk just prior to administration.1 Tablets are not palatable if chewed due to bitter taste of proguanil.17

Dosage

Available as fixed-combination tablets (adult strength) containing 250 mg of atovaquone and 100 mg of proguanil hydrochloride and fixed-combination pediatric tablets containing 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride.1

Dosage expressed in terms of the number of tablets (adult strength or pediatric)1 115 121 134 144 or as dose of atovaquone and dose of proguanil hydrochloride.1

Pediatric Patients

Prevention of Malaria
Oral

Dosage is based on weight.1 115 121 134 (See Table 1.)

Table 1. Pediatric Dosage of Atovaquone/proguanil for Prevention of Malaria1115121134

Weight (kg)

Dosage (Number of Tablets)

Dosage (Atovaquone Dose/Proguanil Hydrochloride Dose)

11–20

1 pediatric tablet once daily

62.5 mg/25 mg once daily

21–30

2 pediatric tablets once daily

125 mg/50 mg once daily

31–40

3 pediatric tablets once daily

187.5 mg/75 mg once daily

>40

1 tablet (adult strength) once daily

250 mg/100 mg once daily

Although safety and efficacy not established for prevention of malaria in pediatric patients weighing <11 kg,1 CDC and other experts state that pediatric patients weighing 5–8 kg can receive ½ of a pediatric tablet once daily (31.3 mg/12.5 mg once daily) and those weighing 9–10 kg can receive 3/4 of a pediatric tablet once daily (46.9 mg/18.8 kg once daily).115 121 134

Initiate prophylaxis 1–2 days prior to entering malarious area and continue during stay and for 7 days after leaving the area.1 115 121 134

If exposure occurred in areas where P. ovale or P. vivax is endemic, terminal prophylaxis with 14-day regimen of primaquine may be indicated;115 134 give during final 7 days of atovaquone/proguanil prophylaxis and then for an additional 7 days or, if not feasible, give for 14 days after atovaquone/proguanil prophylaxis discontinued.115

Presumptive Self-treatment of Malaria
Oral

Use pediatric dosage recommended for treatment of uncomplicated malaria.115 134 (See Table 2.)

Initiate promptly if malaria suspected (fever, chills, or other influenza-like illness) and professional medical care not readily available.115 134

Only a temporary measure; obtain professional medical evaluation as soon as possible.115

Do not use for presumptive self-treatment of malaria in those taking the drug for prophylaxis.115 134

Treatment of Uncomplicated Malaria
Oral

Dosage is based on weight.1 134 144 (See Table 2.)

Table 2. Pediatric Dosage of Atovaquone/proguanil for Treatment of Uncomplicated P. falciparum Malaria1134144

Weight (kg)

Dosage (Number of Tablets)

Dosage (Atovaquone Dose/Proguanil Hydrochloride Dose)

5–8

2 pediatric tablets once daily for 3 consecutive days

125 mg/50 mg

9–10

3 pediatric tablets once daily for 3 consecutive days

187.5 mg/75 mg

11–20

1 tablet (adult strength) once daily for 3 consecutive days

250 mg/100 mg

21–30

2 tablets (adult strength) once daily for 3 consecutive days

500 mg/200 mg

31–40

3 tablets (adult strength) once daily for 3 consecutive days

750 mg/300 mg

>40

4 tablets (adult strength) as a single daily dose for 3 consecutive days

1 g/400 mg

Safety and efficacy not established for treatment of malaria in pediatric patients weighing <5 kg.1

For treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax, CDC and other experts recommend the same dosage used for treatment of uncomplicated P. falciparum malaria.134 144 Because atovaquone/proguanil cannot prevent relapse of P. vivax malaria, 14-day regimen of primaquine indicated in conjunction with atovaquone/proguanil to provide a radical cure.134 143 144

Adults

Prevention of Malaria
Oral

A single tablet (adult strength) once daily (250 mg of atovaquone and 100 mg of proguanil hydrochloride once daily).1 115 121 134

Initiate prophylaxis 1–2 days prior to entering malarious area and continue during stay and for 7 days after leaving the area.1 115 134

If exposure occurred in areas where P. ovale or P. vivax is endemic, terminal prophylaxis with 14-day regimen of primaquine may be indicated;115 134 give during final 7 days of atovaquone/proguanil prophylaxis and then for an additional 7 days or, if not feasible, give for 14 days after atovaquone/proguanil prophylaxis discontinued.115

Presumptive Self-treatment of Malaria
Oral

Use adult dosage recommended for treatment of uncomplicated malaria.115 134

Initiate presumptive self-treatment if malaria suspected (fever, chills, or other influenza-like illness) and professional medical care not readily available.115 134

Only a temporary measure; obtain professional medical evaluation as soon as possible.115

Do not use for presumptive self-treatment of malaria in those taking the drug for prophylaxis.115 134

Treatment of Uncomplicated Malaria
Oral

For treatment of uncomplicated malaria caused by P. falciparum, 4 tablets (adult strength) once daily for 3 consecutive days (1 g of atovaquone and 400 mg of proguanil hydrochloride once daily for 3 consecutive days).1 134 144 To reduce incidence of nausea and vomiting, some clinicians suggest an alternative regimen of 2 tablets (adult strength) twice daily for 3 consecutive days.134

For treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax, CDC and other experts recommend the same dosage used for treatment of uncomplicated P. falciparum malaria.134 144 Because atovaquone/proguanil cannot prevent relapse of P. vivax malaria, 14-day regimen of primaquine indicated in conjunction with atovaquone/proguanil to provide a radical cure.134 143 144

Special Populations

Hepatic Impairment

Dosage adjustments not needed in those with mild to moderate hepatic impairment; data not available regarding use in those with severe hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustments not needed in those with mild to moderate renal impairment (Clcr 30–80 mL/minute).1

Do not use for prevention of malaria in those with severe renal impairment (Clcr <30 mL/minute); use with caution for treatment of malaria in such patients.1 (See Renal Impairment under Cautions.)

Cautions for Atovaquone and Proguanil Hydrochloride

Contraindications

  • Known hypersensitivity reactions (e.g., anaphylaxis, erythema multiforme, Stevens-Johnson syndrome, angioedema, vasculitis) to atovaquone, proguanil, or any ingredient in the formulation.1

  • Prevention of malaria in patients with Clcr <30 mL/minute;1 pancytopenia has been reported in such patients receiving proguanil.1

Warnings/Precautions

Sensitivity Reactions

Allergic reactions, including anaphylaxis, angioedema, urticaria, and vasculitis, reported.1

Photosensitivity, rash, erythema multiforme, and Stevens-Johnson syndrome also reported.1

GI Effects

Nausea, vomiting, or diarrhea reported in 8–12% of adults receiving atovaquone/proguanil for treatment of uncomplicated malaria; vomiting reported in up to 19% of children.1

Atovaquone absorption reduced in patients with vomiting or diarrhea.1 Monitor for parasitemia and consider use of an antiemetic agent.1 (See Specific Drugs under Interactions.)

If severe or persistent vomiting or diarrhea occurs, consider alternative antimalarial.1

Hepatotoxicity

Elevations in liver function test values reported.1

Hepatitis and hepatic failure requiring liver transplantation reported in individuals receiving the drug for prophylaxis.1

Malaria Recrudescence

Do not use to treat recrudescence of malaria or malaria that occurs as a result of failure of treatment or prophylaxis with the drug.1 Use an alternative antimalarial.1

Selection and Use of Antimalarials

Do not use for initial treatment of severe malaria.1 143 Life-threatening, serious, or overwhelming malaria requires aggressive treatment with a parenteral antimalarial regimen.143 144

Not evaluated in patients with cerebral malaria or other manifestations of severe complicated malaria (e.g., hyperparasitemia, pulmonary edema, renal failure).1

Specific Populations

Pregnancy

Category C.1

Manufacturer states use in pregnant women only if potential benefits justify risks to the fetus.1

CDC states use may be considered in pregnant women for treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum when other treatment options not available or not tolerated and if potential benefits outweigh risks.143 CDC states do not use for prevention of malaria in pregnant women.115

Lactation

Atovaquone distributed into milk in rats; proguanil distributed into human milk.1

Manufacturer states use with caution in nursing women.1

CDC states may be used for treatment of malaria in women breast-feeding infants of any weight when potential benefits outweigh possible risks to the infant (e.g., when a breast-feeding woman has acquired P. falciparum malaria in area with multidrug-resistant malaria and other treatment options not tolerated).115 CDC states do not use for prevention of malaria in women breast-feeding infants who weigh <5 kg.115

Pediatric Use

Safety and efficacy for prevention of malaria not established in children weighing <11 kg.1

Safety and efficacy for treatment of malaria not established in children weighing <5 kg.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.1

Consider the greater frequency of decreased hepatic, renal, and/or cardiac function, higher systemic exposure to cycloguanil (active metabolite of proguanil), and greater frequency of concomitant disease or drug therapy observed in geriatric individuals.1

Hepatic Impairment

Pharmacokinetics not studied in patients with severe hepatic impairment.1

Renal Impairment

Contraindicated for prevention of malaria if Clcr <30 mL/minute.

Use with caution for treatment of malaria if Clcr <30 mL/minute and only if benefits outweigh risks (e.g., increased drug concentrations).1

Common Adverse Effects

Abdominal pain, nausea, vomiting, headache, diarrhea, asthenia, anorexia, dizziness, cough, and pruritus.1

Interactions for Atovaquone and Proguanil Hydrochloride

Proguanil metabolized principally by CYP2C19; potential pharmacokinetic interactions with drugs that are substrates or inhibitors of CYP2C19.1

Specific Drugs

Drug

Interaction

Comments

Antimycobacterials, rifamycins (rifabutin, rifampin)

Decreased atovaquone concentrations1

Concomitant use not recommended1

Indinavir

Decreased trough concentrations of indinavir; no effect on peak concentrations or AUC of indinavir1

Use with caution1

Metoclopramide

Decreased bioavailability of atovaquone1

Use concomitantly only if other antiemetics not available1

Tetracycline

Decreased atovaquone concentrations1

Closely monitor parasitemia1

Warfarin

Possible potentiation of anticoagulant effects of warfarin1

Use concomitantly with caution; monitor coagulation parameters1

Atovaquone and Proguanil Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Oral bioavailability of atovaquone shows considerable interindividual variation;1 absorption of atovaquone may be reduced in patients with diarrhea and vomiting.1

Proguanil hydrochloride extensively absorbed from GI tract.1

Food

Administration with dietary fat increases rate and extent of GI absorption of atovaquone;1 absolute bioavailability is 23% when taken with food.1

Distribution

Extent

Atovaquone distributed into milk in rats; not known whether distributed into human milk.1

Small amounts of proguanil distributed into milk.1

Plasma Protein Binding

Atovaquone >99% bound to plasma proteins; proguanil 75% bound to plasma proteins.1

Elimination

Metabolism

There is indirect evidence that atovaquone may undergo limited metabolism; however, a specific metabolite(s) has not been identified.1 Proguanil metabolized principally by CYP2C19 to the active metabolite cycloguanil and to 4-chlorophenylbiguanide.1

Elimination Route

Following oral administration in healthy individuals, >94% of a dose of atovaquone excreted unchanged in feces; 40–60% of a dose of proguanil excreted in urine.1

Half-life

Atovaquone: Elimination half-life about 2–3 days in adults and 1–2 days in pediatric patients.1

Proguanil: Elimination half-life 12–21 hours in adult and pediatric patients;1 may be longer in slow metabolizers.1

Special Populations

In patients with mild to moderate hepatic impairment, there were no marked differences in rate or extent of systemic exposure to atovaquone, although elimination half-life of atovaquone was prolonged in individuals with moderate hepatic impairment.1 In patients with mild to moderate hepatic impairment, extent of systemic exposure to proguanil was increased and elimination half-life prolonged, with resultant decrease in systemic exposure to cycloguanil and increase in elimination half-life of this metabolite.1

Pharmacokinetics of atovaquone and proguanil in patients with mild renal impairment (Clcr 50–80 mL/minute) similar to that in those with normal renal function.1 In patients with moderate renal impairment (Clcr 30–50 mL/minute), oral clearance of atovaquone unaffected but proguanil oral clearance reduced approximately 35%.1

In patients with severe renal impairment (Clcr <30 mL/minute), systemic exposure to atovaquone was decreased and elimination half-lives of proguanil and cycloguanil were increased, resulting in potential for drug accumulation and toxicity with repeated dosing.1

In geriatric individuals (65–79 years of age), extent of systemic exposure to cycloguanil (active metabolite of proguanil) was increased, and average elimination half-life prolonged (mean: 14.9 hours) compared with younger adults (mean: 8.3 hours).1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions and Spectrum

  • Atovaquone/proguanil is a fixed combination of 2 antimalarial agents.1 3 4 5 6 7 8 9 10 13 14 15 Atovaquone is a hydroxynaphthoquinone derivative4 5 and proguanil hydrochloride is a biguanide derivative.1 3 4 5 6 7 8 9 10 13 14 15

  • Atovaquone selectively inhibits mitochondrial electron transport in plasmodia and collapses mitochondrial membrane potential.1 5 6 7 8 10 Antimalarial activity of proguanil principally due to its active metabolite (cycloguanil);1 4 6 7 cycloguanil inhibits dihydrofolate reductase, leading to depletion of pyrimidine nucleotide pools and disruption in nucleic acid synthesis and cell replication.1 4 6 10

  • Atovaquone and proguanil synergistic against erythrocytic stages of Plasmodium.5 6 7 13 Proguanil may lower concentration of atovaquone needed to collapse mitochondrial membrane potential.15

  • Active against erythrocytic forms of most strains of Plasmodium falciparum, P. malariae, P. ovale, and P. vivax1 8 and exoerythrocytic forms of Plasmodium;1 no activity against P. vivax hypnozoites.3 8

  • P. falciparum with decreased susceptibility to atovaquone or to proguanil/cycloguanil can be selected in vitro or in vivo.1

Advice to Patients

  • Importance of taking atovaquone/proguanil at same time each day with food or milky drink.1

  • Advise patients to repeat a dose if vomiting occurs within 1 hour after ingestion.1

  • If a dose is missed, take missed dose as soon as it is remembered.1 If dose is skipped, do not take a double dose to make up for the missed dose.1

  • Advise patients of risk of rare serious adverse effects including hepatitis, severe skin reactions, neurologic events, or hematologic events.1

  • Importance of consulting a health-care professional regarding other prophylactic regimens if atovaquone/proguanil is discontinued for any reason.1

  • Necessity of taking protective measures to reduce contact with mosquitoes (protective clothing, insect repellents, mosquito nets, remaining in air-conditioned or well-screened areas).1 115

  • Possibility of contracting malaria during travel, regardless of prophylactic regimen used.1 115

  • Importance of seeking medical attention as soon as possible if febrile illness develops during or after return from a malaria-endemic area and of informing clinician of possible malaria exposure, including instances when such illness was self-treated as malaria during travel.1 115

  • Advise travelers that presumptive self-treatment of malaria is an interim measure and that they should seek medical evaluation as soon as possible.115

  • Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of discussing with clinician the risks and benefits of travel to malaria-endemic areas during pregnancy.1 Compared with other populations, pregnant women have higher risk of death and serious complications of falciparum malaria.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Atovaquone and Proguanil Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

62.5 mg of atovaquone and 25 mg of proguanil hydrochloride

Atovaquone and Proguanil Hydrochloride Pediatric

Glenmark

Malarone Pediatric

GlaxoSmithKline

250 mg of atovaquone and 100 mg of proguanil hydrochloride

Malarone

GlaxoSmithKline

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions March 4, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. GlaxoSmithKline. Malarone (atovaquone and proguanil hydrochloride) tablets and pediatric tablets prescribing information. Research Triangle Park, NC; 2013 Jun.

3. Anon. Atovaquone and proguanil hydrochloride: a new antimalarial combination. WHO Drug Information. 1999; 13:226-227.

4. Parfitt K, ed. Martindale: the complete drug reference. 32nd ed. London: The Pharmaceutical Press; 1999:422-42.

5. Shanks GD, Gordon DM, Klotz FW et al. Efficacy and safety of atovaquone/proguanil as suppressive prophylaxis for Plasmodium falciparum malaria. Clin Infect Dis. 1998; 27:494-9. [IDIS 419667] [PubMed 9770146]

6. Sukwa TY, Mulenga M, Chisdaka N et al. A randomized, double-blind, placebo-controlled field trial to determine the efficacy and safety of Malarone (atovaquone/proguanil) for the prophylaxis of malaria in Zambia. Am J Trop Med Hyg. 1999; 60:521-25. [IDIS 428139] [PubMed 10348223]

7. Bustos DG, Canfield CJ, Canete-Miquel E et al. Atovaquone-proguanil compared with chloroquine and chloroquine-sulfadoxine-pyrimethamine for treatment of acute Plasmodium falciparum malaria in the Philippines. J Infect Dis. 1999; 179:1587-90. [IDIS 430232] [PubMed 10228090]

8. Looareesuwan S, Chulay JD, Canfield CJ et al. Malarone (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Am J Trop Med Hyg. 1999; 60:533-43. [IDIS 428141] [PubMed 10348225]

9. Lell B, Luckner D, Ndjaveé M et al. Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. Lancet. 1998; 351:709-13. [IDIS 402024] [PubMed 9504515]

10. van der Berg JD, Duvenage CSJ, Roskell NS et al. Safety and efficacy of atovaquone and proguanil hydrochloride for the prophylaxis of Plasmodium falciparum malaria in South Africa. Clin Ther. 1999; 21:741-9. [IDIS 428169] [PubMed 10363739]

13. Looareesuwan S, Wilairatana P, Chalermarut K et al. Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg. 1999; 60:526-32. [IDIS 428140] [PubMed 10348224]

14. Anabwani G, Canfield CJ, Hitchinson DBA. Combination atovaquone and proguanil hydrochloride vs halofantrine for treatment of acute Plasmodium falciparum malaria in children. Ped Infect Dis. 1999; 18:456-61.

15. Srivastava IK, Vaidya AB. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother. 1999; 43:1334-9. [PubMed 10348748]

17. Glaxo Wellcome, Research Triangle Park, NC: Personal communication.

115. Centers for Disease Control and Prevention. CDC health information for international travel, 2014. Atlanta, GA: US Department of Health and Human Services. Updates may be available at CDC website.

121. . Advice for travelers. Treat Guidel Med Lett. 2012; 10:45-56. [PubMed 22777212]

134. Anon. Drugs for parasitic infections. Treat Guidel Med Lett. 2010; 8:e1-16.

143. Centers for Disease Control and Prevention. CDC treatment guidelines: Treatment of malaria (guidelines for clinicians). 2013 Jul. From the CDC website. Accessed 2013 Sep 27.

144. Centers for Disease Control and Prevention. Guidelines for treatment of malaria in the United States (based on drugs currently available for use in the United States–updated July 1, 2013). From the CDC website. Accessed 2013 Sep 27.

161. World Health Organization (WHO). Guidelines for the treatment of malaria. 2nd edition. Geneva, Switzerland: World Health Organization; 2010. Updates may be available at WHO website.

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