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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 2 antimalarials (atovaquone, proguanil).1

Uses for Atovaquone and Proguanil Hydrochloride

Malaria

Prevention (prophylaxis) of malaria caused by Plasmodium falciparum, including chloroquine-resistant strains.1 2 5 6 9 10 11 18 19 Recommended by CDC and others as a drug of choice for prophylaxis in individuals traveling to areas where chloroquine-resistant P. falciparum malaria has been reported;2 11 19 recommended by CDC as an alternative in those traveling to areas where chloroquine-resistant P. falciparum has not been reported.11

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Treatment of acute, uncomplicated malaria caused by P. falciparum, including malaria acquired in areas where chloroquine resistance has been reported;1 2 7 8 13 14 18 21 has been effective in regions with multidrug-resistant P. falciparum malaria.1 18 Recommended by CDC as a drug of choice for treatment of uncomplicated chloroquine-resistant P. falciparum malaria.21

Presumptive self-treatment of malaria in travelers who elect not to use prophylaxis, those who require or choose to use a prophylaxis regimen that may not have optimal efficacy, or for long-term travelers receiving effective prophylaxis who plan to visit very remote areas.2 11 18 Recommended by CDC and others as drug of choice for such treatment.2 11

One of several regimens recommended by CDC for treatment of uncomplicated chloroquine-resistant P. vivax malaria.21

Active only against the 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;3 4 11 primaquine usually also indicated to eradicate hypnozoites and prevent relapse in patients exposed to or being treated for P. ovale or P. vivax malaria.11

Detailed recommendations regarding prevention of malaria available from CDC 24 hours a day from the voice information service (877-394-8747) or at .11

Assistance with diagnosis or treatment of malaria available by contacting CDC Malaria Hotline at 770-488-7788 from 8:00 a.m. to 4:30 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after hours, on weekends, and holidays.21

Atovaquone and Proguanil Hydrochloride Dosage and Administration

Administration

Oral Administration

Administer orally with food or milky drink.1 2 18

Usually once daily as a single dose, given at the same time each day.1 18 When used for treatment of malaria, nausea and vomiting may be reduced by administering the daily dose in 2 equally divided doses.2

If vomiting occurs within 1 hour of ingestion, repeat 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 containing atovaquone and proguanil hydrochloride; dosage expressed in terms of both drugs.1

Pediatric Patients

Prevention of Malaria
Oral
Pediatric Dosage for Prevention of Malaria121118

Weight (kg)

Daily Dosage (Atovaquone/Proguanil HCL)

Dosage Regimen

11–20

62.5 mg/25 mg

1 pediatric tablet daily

21–30

125 mg/50 mg

2 pediatric tablets once daily

31–40

187.5 mg/75 mg

3 pediatric tablets once daily

>40

250 mg/100 mg

1 adult tablet daily

Initiate prophylaxis 1–2 days prior to entering the malarious area and continue for 7 days after leaving the area.1 2 11 18 19

Terminal prophylaxis with primaquine may also be indicated if exposure occurred in areas where P. ovale or P. vivax are endemic.2 11 Primaquine terminal prophylaxis generally is administered during the final 7 days of the atovaquone and proguanil regimen and then for an additional 7 days or, alternatively, for 14 days after the drug is discontinued.11

Treatment of Uncomplicated Malaria
Oral
Pediatric Dosage for Treatment of Acute, Uncomplicated Malaria121820

Weight (kg)

Daily Dosage (Atovaquone/Proguanil HCL)

Dosage Regimen

5–8

125 mg/50 mg

2 pediatric tablets daily for 3 consecutive days

9–10

187.5 mg/75 mg

3 pediatric tablets daily for 3 consecutive days

11–20

250 mg/100 mg

1 adult tablet daily for 3 consecutive days

21–30

500 mg/200 mg

2 adult tablets once daily for 3 consecutive days

31–40

750 mg/300 mg

3 adult tablets once daily for 3 consecutive days

>40

1 g/400 mg

4 adult tablets as a single daily dose for 3 consecutive days or 2 adult tablets twice daily for 3 consecutive days

Presumptive Self-treatment of Malaria
Oral

Use usual pediatric dosage recommended for treatment of uncomplicated malaria.2 11 18 Initiate presumptive self-treatment if malaria is suspected (fever, chills, or other influenza-like illness) and professional medical care will not be available within 24 hours.11 18

Not recommended for presumptive self-treatment of malaria in those currently taking the drug for prophylaxis.11

Adults

Prevention of Malaria
Oral

250 mg of atovaquone and 100 mg of proguanil hydrochloride (1 adult tablet) once daily.1 2 11 18 19

Initiate prophylaxis 1–2 days prior to entering the malarious area and continue for 7 days after leaving the area.1 2 11 18

Terminal prophylaxis with primaquine may also be indicated if exposure occurred in areas where P. ovale or P. vivax are endemic.2 11 Primaquine terminal prophylaxis generally is administered during the final 7 days of the atovaquone and proguanil regimen and then for an additional 7 days or, alternatively, for 14 days after the drug is discontinued.11

Treatment of Uncomplicated Malaria
Oral

1 g of atovaquone and 400 mg of proguanil hydrochloride (4 adult tablets) once daily for 3 consecutive days.1 2 20 Alternatively, 500 mg of atovaquone and 200 mg of proguanil hydrochloride (2 adult tablets) every 12 hours for 3 consecutive days.2

Presumptive Self-treatment of Malaria
Oral

Use usual adult dosage recommended for the treatment of malaria.2 11 18 Initiate presumptive self-treatment if malaria is suspected (fever, chills, or other influenza-like illness) and professional medical care will not be available within 24 hours.11 18

Not recommended for presumptive self-treatment of malaria in those currently taking the drug for prophylaxis.11

Special Populations

Renal Impairment

No dosage adjustments needed in those with mild to moderate renal impairment (Clcr 30–80 mL/minute).1

Geriatric Patients

Cautious dosage adjustment recommended.1

Cautions for Atovaquone and Proguanil Hydrochloride

Contraindications

  • Known hypersensitivity to atovaquone, proguanil, or any ingredient in the formulation.1

  • Prevention of malaria in patients with Clcr <30 mL/minute.1

Warnings/Precautions

Sensitivity Reactions

Anaphylaxis reported rarely.1 8 17

Erythema multiforme and Stevens-Johnson syndrome reported rarely.1 19 Rash and urticaria also reported.1

General Precautions

Hepatic Effects

Elevations in liver function test values reported.1 Hepatitis reported rarely.1 Hepatic failure requiring liver transplantation reported in at least one individual receiving the drug for prophylaxis.1

GI Effects

Atovaquone absorption reduced in patients with vomiting or diarrhea.1 Monitor for parasitemia and consider administration of an antiemetic agent.1 (See Drug Interactions: Metoclopramide.) Consider alternative antimalarial therapy if severe or persistent vomiting or diarrhea occurs.1

Severe Malaria

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

Prior Use

Repeated use not recommended following failure of the drug for treatment of malaria.1

Should not be used for treatment of malaria (including presumptive self-treatment) in patients who received the drug for prophylaxis of malaria.11 18

Other Precautions

Do not administer with other preparations containing proguanil.1

Specific Populations

Pregnancy

Category C.1

May be used in pregnant women if the potential benefits outweigh the possible risks to the fetus.1 18 CDC states that the drug may be used in pregnant women for treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum if other treatment options are not available or are not tolerated and if potential benefits outweigh risks.21 However, CDC states do not use for prevention of malaria in pregnant women.11

Lactation

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

Caution advised.1 May be used for treatment of malaria in women breast-feeding infants of any weight when the potential benefits outweigh the possible risks to the infant (e.g., when a breast-feeding woman has acquired P. falciparum malaria in an area with multidrug-resistant malaria and other treatment options are not tolerated).11 However, CDC states the drug should not be used for prevention of malaria in women breast-feeding infants who weigh <5 kg.11

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 20

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

Hepatic Impairment

Use with caution in severe hepatic impairment.17

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 other substrates or inhibitors of this enzyme unknown.1

Protein-Bound Drugs

Pharmacokinetic interaction unlikely.1

Specific Drugs

Drug

Interaction

Comments

Antimycobacterials, rifamycins (rifabutin, rifampin)

Decreased plasma atovaquone concentrations1

Concomitant use not recommended1

Indinavir

Decreased trough concentrations of indinavir; no change in peak plasma concentrations or AUC of indinavir1

Use with caution1

Metoclopramide

Decreased bioavailability of atovaquone1

Use concomitantly only if other antiemetics not available1

Tetracycline

Decreased plasma atovaquone concentrations1

Closely monitor parasitemia1

Warfarin

Possible potentiation of the anticoagulant effects of warfarin1

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 the GI tract.1

Food

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

GI absorption of proguanil hydrochloride not affected by food.1

Distribution

Extent

Atovaquone distributed into milk in rats; not known whether the drug distributed into human milk.1 Small amounts of proguanil are distributed into milk.1

Plasma Protein Binding

Atovaquone is >99% bound to plasma proteins; proguanil is 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 is about 2–3 days in adults and 1–2 days in pediatric patients.1

Proguanil: Elimination half-life is 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 the rate or extent of systemic exposure to atovaquone, although the elimination half-life of atovaquone was prolonged in individuals with moderate hepatic impairment.1 In patients with mild to moderate hepatic impairment, the extent of systemic exposure to proguanil was increased and the elimination half-life was prolonged, with a resultant decrease in systemic exposure to cycloguanil and an increase in the 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 the potential for drug accumulation and toxicity with repeated dosing.1

In geriatric individuals (65–79 years of age), the extent of systemic exposure to cycloguanil (active metabolite of proguanil) was increased, and the average elimination half-life was 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

  • A fixed combination of 2 antimalarial agents: atovaquone (a hydroxynaphthoquinone derivative)4 5 and proguanil hydrochloride (a biguanide derivative).1 2 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 and proguanil at the same time each day with food or milky drink.1

  • Importance of repeating dose if vomiting occurs within 1 hour of ingestion.1

  • Importance of consulting clinician regarding alternative prophylaxis regimens if atovaquone and proguanil prophylaxis 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 11

  • Possibility of contracting malaria during travel, regardless of prophylactic regimen used.1 11

  • Advise travelers who plan presumptive self-treatment in the event of a possible malarial infection to keep an amount of atovaquone and proguanil sufficient for self-treatment in their possession during travel and to take it promptly in the event of a febrile illness during or after their travel if professional medical care is not readily available.2

  • Advise travelers that presumptive self-treatment of malaria is an interim measure and that they should seek medical evaluation as soon as possible.11 18

  • 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 11

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

  • Importance of notifying clinician of existing or contemplated therapy, including prescription and OTC drugs1 and herbal or dietary supplements, and any concomitant illnesses.

  • 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

Malarone Pediatric

GlaxoSmithKline

250 mg of atovaquone and 100 mg of proguanil hydrochloride

Malarone

GlaxoSmithKline

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 1, 2010. 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; 2008 Jun.

2. Anon. Drugs for parasitic infections. From the Medical Letter website (). Aug 2008.

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]

11. Centers for Disease Control and Prevention. Health information for international travel, 2010. Atlanta, GA: US Department of Health and Human Services; 2010. Updates available from CDC website ().

12. WHO. International travel and health: vaccination requirements and health advice- situation as of Jan 1, 2000. Geneva: WHO; 2000:67-85.

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.

18. Centers for Disease Control and Prevention. Information for health care providers: Malarone for malaria treatment and prophylaxis. From CDC web site (). Accessed Sept 25, 2003.

19. Anon. Advice for travelers. Med Lett Treat Guid. 2006; 45:25-34.

20. Centers for Disease Control and Prevention. CDC treatment guidelines: Treatment of malaria (guidelines for clinicians). 2007 Mar. From the CDC website.

21. 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). From the CDC website. Accessed 2009 Jul 1.

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