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Atovaquone and Proguanil

Medically reviewed by Drugs.com. Last updated on Aug 30, 2020.

Pronunciation

(a TOE va kwone & pro GWA nil)

Index Terms

  • Atovaquone and Proguanil Hydrochloride
  • Atovaquone/Proguanil HCl
  • Proguanil and Atovaquone
  • Proguanil Hydrochloride and Atovaquone

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Malarone: Atovaquone 250 mg and proguanil hydrochloride 100 mg

Generic: Atovaquone 250 mg and proguanil hydrochloride 100 mg

Tablet, Oral [pediatric]:

Malarone: Atovaquone 62.5 mg and proguanil hydrochloride 25 mg

Generic: Atovaquone 62.5 mg and proguanil hydrochloride 25 mg

Brand Names: U.S.

  • Malarone

Pharmacologic Category

  • Antimalarial Agent

Pharmacology

Atovaquone: Selectively inhibits parasite mitochondrial electron transport.

Proguanil: The metabolite cycloguanil inhibits dihydrofolate reductase, disrupting deoxythymidylate synthesis. Together, atovaquone/cycloguanil affect the erythrocytic and exoerythrocytic stages of development.

Absorption

Atovaquone: The rate and extent of absorption is increased when administered with dietary fat.

Proguanil: Extensive

Distribution

Vd:

Atovaquone: Children and Adults: ~8.8 L/kg

Proguanil: Children >15 years and Adults and 31-110 kg: 1617-2502 L; Pediatric patients ≤15 years and 11-56 kg: 462-966 L; concentrated in erythrocytes

Metabolism

Proguanil: Hepatic to active metabolites, cycloguanil (via CYP2C19) and 4-chlorophenylbiguanide

Excretion

Atovaquone: Feces (>94% as unchanged drug); urine (<0.6%)

Proguanil: Urine (40% to 60%)

Half-Life Elimination

Atovaquone: 2-3 days (adults), 1-2 days (children)

Proguanil: 12-21 hours

Protein Binding

Atovaquone: >99%

Proguanil: 75%

Special Populations: Renal Function Impairment

In patients with moderate renal impairment (CrCl 30-50 mL/minute), mean oral clearance for proguanil was reduced by ~35% compared with patients with normal renal function CrCl >80 mL/minute). In patients with severe renal impairment (CrCl <30 mL/minute), atovaquone Cmax and AUC are reduced, but the elimination half-lives for proguanil and cycloguanil are prolonged, with corresponding increases in AUC, resulting in the potential of drug accumulation and toxicity with repeated dosing.

Special Populations: Hepatic Function Impairment

Atovaquone elimination half-life was increased in patients with moderate hepatic impairment. Proguanil AUC, Cmax, and elimination half-life were increased and cycloguanil (metabolite) AUC and Cmax were decreased and elimination half-life was increased in patients with mild hepatic impairment. Proguanil AUC and Cmax were increased in patients with moderate hepatic impairment. The pharmacokinetics of atovaquone, proguanil, and cycloguanil have not been studied in patients with severe hepatic impairment.

Special Populations: Elderly

AUC was increased, Tmax was longer, and elimination half-life was longer in elderly subjects (~15 hours) compared to younger subjects (~8 hours).

Use: Labeled Indications

Malaria, prophylaxis: Prophylaxis of Plasmodium falciparum malaria, including areas where chloroquine resistance has been reported. Note: CDC also recommends atovaquone/proguanil as prophylaxis for other Plasmodium species (CDC Yellow Book 2020).

Malaria, treatment: Treatment of acute, uncomplicated P. falciparum malaria. Note: CDC guidelines also recommend atovaquone/proguanil as an alternative agent for chloroquine-sensitive Plasmodium species, for chloroquine-resistant Plasmodium vivax or Plasmodium ovale, and as alternative oral treatment for severe malaria after completion of IV therapy or as interim therapy pending IV therapy (CDC 2020).

Contraindications

Hypersensitivity to atovaquone, proguanil, or any component of the formulation; prophylactic use in severe renal impairment (CrCl <30 mL/minute)

Dosing: Adult

Malaria, prophylaxis: Oral: 1 tablet (atovaquone 250 mg/proguanil 100 mg per tablet) once daily; start 1 to 2 days prior to entering a malaria-endemic area, continue throughout the stay and for 7 days after returning (CDC Yellow Book 2020).

Malaria, treatment: Oral: 4 tablets (atovaquone 250 mg/proguanil 100 mg per tablet) once daily for 3 days. Note: If used for P. vivax or P. ovale, use in combination with primaquine. If used for severe malaria (after completion of IV therapy), use full 3-day schedule (CDC 2020).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Tablets are available in different strengths (pediatric and adult tablets) and both may be used in pediatric patients depending upon patient weight; use extra precaution

Malaria; prevention (Yellow Book [CDC 2018]): Infants, Children, and Adolescents: Begin 1 to 2 days prior to entering a malaria-endemic area, continue throughout the stay and for 7 days after leaving area: Oral:

5 to 8 kg: Pediatric tablet (62.5 mg atovaquone/25 mg proguanil per tablet): 31.25 mg atovaquone/12.5 mg proguanil (1/2 tablet) once daily

>8 to 10 kg: Pediatric tablet (62.5 mg atovaquone/25 mg proguanil per tablet): 46.88 mg atovaquone/18.75 mg proguanil (3/4 tablet) once daily

>10 to 20 kg: Pediatric tablet (62.5 mg atovaquone/25 mg proguanil per tablet): 62.5 mg atovaquone/25 mg proguanil (1 tablet) once daily

>20 to 30 kg: Pediatric tablet (62.5 mg atovaquone/25 mg proguanil per tablet): 125 mg atovaquone/50 mg proguanil (2 tablets) once daily

>30 to 40 kg: Pediatric tablet (62.5 mg atovaquone/25 mg proguanil per tablet): 187.5 mg atovaquone/75 mg proguanil (3 tablets) once daily

>40 kg: Adult tablet (250 mg atovaquone/100 mg proguanil per tablet): 250 mg atovaquone/100 mg proguanil (1 tablet) once daily

Malaria; treatment, uncomplicated P. falciparum or P. vivax (CDC 2013): Infants, Children, and Adolescents: Oral:

5 to 8 kg: Pediatric tablet (62.5 mg atovaquone/25 mg proguanil per tablet): 125 mg atovaquone/50 mg proguanil (2 tablets) once daily for 3 doses

9 to 10 kg: Pediatric tablet (62.5 mg atovaquone/25 mg proguanil per tablet): 187.5 mg atovaquone/75 mg proguanil (3 tablets) once daily for 3 doses

11 to 20 kg: Adult tablet (250 mg atovaquone/100 mg proguanil per tablet): 250 mg atovaquone/100 mg proguanil (1 tablet) once daily for 3 doses

21 to 30 kg: Adult tablet (250 mg atovaquone/100 mg proguanil per tablet): 500 mg atovaquone/proguanil/200 mg proguanil (2 tablets) once daily for 3 doses

31 to 40 kg: Adult tablet (250 mg atovaquone/100 mg proguanil per tablet): 750 mg atovaquone/300 mg proguanil (3 tablets) once daily for 3 doses

>40 kg: Adult tablet (250 mg atovaquone/100 mg proguanil per tablet): 1,000 mg atovaquone/400 mg proguanil (4 tablets) once daily for 3 doses

Administration

Administer with food or milk-based drink at the same time each day. If vomiting occurs within 1 hour of administration, repeat the dose. For patients who have difficulty swallowing tablets, tablets may be crushed and mixed with condensed milk just prior to administration.

Dietary Considerations

Must be taken with food or milk-based drink.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Antihepaciviral Combination Products: May decrease the serum concentration of Proguanil. Monitor therapy

Antipsychotic Agents (Phenothiazines): Antimalarial Agents may increase the serum concentration of Antipsychotic Agents (Phenothiazines). Monitor therapy

Artemether: May enhance the adverse/toxic effect of Antimalarial Agents. Management: Artemether/Lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. Avoid combination

CYP2C19 Inhibitors (Moderate): May decrease serum concentrations of the active metabolite(s) of Proguanil. CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Proguanil. Monitor therapy

CYP2C19 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of Proguanil. CYP2C19 Inhibitors (Strong) may increase the serum concentration of Proguanil. Monitor therapy

Dapsone (Systemic): May enhance the adverse/toxic effect of Antimalarial Agents. Specifically, concomitant use of dapsone with antimalarial agents may increase the risk for hemolytic reactions. Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Systemic). Specifically, concomitant use of antimalarial agents with dapsone may increase the risk of hemolytic reactions. Management: Closely monitor patients for signs/symptoms of hemolytic reactions with concomitant use of dapsone and antimalarial agents, particularly in patients deficient in glucose-6-phosphate dehydrogenase (G6PD), methemoglobin reductase, or with hemoglobin M. Consider therapy modification

Dapsone (Topical): Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Topical). Specifically, the risk of hemolytic reactions may be increased. Management: Closely monitor for signs/symptoms of hemolytic reactions with concomitant use of topical dapsone and antimalarial agents. Patients with glucose-6-phosphate dehydrogenase deficiency may be at particularly high risk for adverse hematologic effects. Consider therapy modification

Efavirenz: May decrease the serum concentration of Atovaquone. Management: Consider alternatives to the use of atovaquone with efavirenz when possible. If this combination must be used, monitor for evidence of reduced atovaquone clinical effectiveness. Consider therapy modification

Ethinyl Estradiol: May diminish the therapeutic effect of Proguanil. Monitor therapy

Etoposide: Atovaquone may increase the serum concentration of Etoposide. Management: Consider separating the administration of atovaquone and etoposide by at least 1 to 2 days. Monitor therapy

Etoposide Phosphate: Atovaquone may increase the serum concentration of Etoposide Phosphate. Management: Consider separating the administration of atovaquone and etoposide by at least 1 to 2 days. Monitor therapy

Indinavir: Atovaquone may decrease the serum concentration of Indinavir. Monitor therapy

Lumefantrine: Antimalarial Agents may enhance the adverse/toxic effect of Lumefantrine. Management: Artemether/Lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. Avoid combination

Metoclopramide: May decrease the serum concentration of Atovaquone. Management: Consider alternatives to metoclopramide when possible; atovaquone should only be used with metoclopramide if no other antiemetics are available. Consider therapy modification

Pyrimethamine: May enhance the adverse/toxic effect of Proguanil. Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Atovaquone. Avoid combination

Ritonavir: May decrease the serum concentration of Atovaquone. Monitor therapy

Ritonavir: May decrease the serum concentration of Proguanil. Monitor therapy

Tetracycline (Systemic): May decrease the serum concentration of Atovaquone. Monitor therapy

Typhoid Vaccine: Proguanil may diminish the therapeutic effect of Typhoid Vaccine. This applies only to the oral (live) typhoid vaccine. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with proguanil. When possible, proguanil should not be started within 10 days of the last vaccine dose. Consider therapy modification

Warfarin: Proguanil may enhance the anticoagulant effect of Warfarin. Monitor therapy

Adverse Reactions

The following adverse reactions were reported in patients being treated for malaria. When used for prophylaxis, reactions are similar to those seen with placebo.

>10%:

Gastrointestinal: Abdominal pain (17%), nausea (12%), vomiting (children: 10% to 13%; adults: 12%)

Hepatic: Increased serum ALT (27%; increased liver function test values typically normalized after ~ 4 weeks), increased serum AST (17%; increased liver function test values typically normalized after ~4 weeks)

1% to 10%:

Central nervous system: Headache (10%), dizziness (5%)

Dermatologic: Pruritus (children: 6%)

Gastrointestinal: Diarrhea (children: 6%; adults: 8%), anorexia (5%)

Neuromuscular & skeletal: Weakness (8%)

<1%, postmarketing, and/or case reports: Anaphylaxis (rare), anemia (rare), angioedema, cholestasis, erythema multiforme (rare), hallucination, hepatic failure (case report), hepatitis (rare), neutropenia, pancytopenia (with severe renal impairment), psychotic reaction (rare), seizure (rare), skin photosensitivity, skin rash, Stevens-Johnson syndrome (rare), stomatitis, urticaria, vasculitis (rare)

Warnings/Precautions

Concerns related to adverse events:

• Hepatic effects: Increased transaminase levels and hepatitis have been reported with prophylactic use; single case report of hepatic failure requiring transplantation documented. Monitor closely and use caution in patients with existing hepatic impairment. Elevations in AST/ALT may persist for up to 4 weeks following treatment (Looareesuwan, 1999).

Disease-related concerns:

• Diarrhea/vomiting: Absorption of atovaquone may be decreased in patients who have diarrhea or vomiting; monitor closely and consider use of an antiemetic. If severe, consider use of an alternative antimalarial.

• Malaria: Appropriate use: Not indicated for cerebral malaria or other severe manifestations of complicated malaria. Delayed cases of P. falciparum malaria may occur after stopping prophylaxis; travelers returning from endemic areas who develop febrile illnesses should be evaluated for malaria. Recrudescent infections or infections following prophylaxis with this agent should be treated with alternative agent(s).

• Renal impairment: Use with caution in patients with preexisting renal disease. May use with caution for treatment of malaria in patients with severe renal impairment (CrCl <30 mL/minute) if benefit outweighs risk. Contraindicated for prophylactic use in severe renal impairment due to the risk of pancytopenia in patients with severe renal impairment treated with proguanil.

Special populations:

• Obesity: Treatment failures have been reported in patients >100 kg (case reports); follow-up monitoring is recommended (Durand, 2008).

Monitoring Parameters

Liver and renal function; closely monitor response to treatment in patients with vomiting or diarrhea and in patients >100 kg (Durand, 2008)

Pregnancy Considerations

Outcome information following maternal use of atovaquone and proguanil in pregnancy is limited (Andrejko 2019; Mayer 2018; Pasternak 2011).

The pharmacokinetics of atovaquone and proguanil may be altered during pregnancy (Burger 2016).

Malaria infection in pregnant women may be more severe than in nonpregnant women and has a high risk of maternal and perinatal morbidity and mortality. Malaria infection during pregnancy can lead to miscarriage, premature delivery, low birth weight, congenital infection, and/or perinatal death. Therefore, pregnant women and women who are likely to become pregnant are advised to avoid travel to malaria-risk areas. When travel is unavoidable, pregnant women should take precautions to avoid mosquito bites and use effective prophylactic medications (CDC 2020; CDC Yellow Book 2020).

Due to limited information, atovaquone/proguanil is not preferred for use during pregnancy. However, atovaquone/proguanil may be used as an alternative treatment of malaria in pregnant women when other treatment options are not available or not being tolerated; consult current CDC guidelines (CDC 2020).

Patient Education

What is this drug used for?

• It is used to treat or prevent malaria.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache

• Cough

• Nausea

• Vomiting

• Diarrhea

• Abdominal pain

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.

• Fever

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.