ATC Class:P01AX06

VA Class:AP101

AHFS Class:

• Antimalarials 8:30.08

Generic Name(s):

• Atovaquone and Proguanil Hydrochloride

• Atovaquone

• Proguanil Hydrochloride

Chemical Name:

• trans 2-[4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione

• 1-( p -Chlorophenyl)-5-isopropylbiguanide hydrochloride

Molecular Formula:

• C₂₂H₁₉ClO₃

• C₁₁H₁₆ClN₅•HCl

Atovaquone and proguanil hydrochloride (atovaquone/proguanil) is a fixed combination of 2 antimalarial agents;1 atovaquone is a hydroxynaphthoquinone derivative and proguanil is a biguanide derivative.161

Atovaquone and proguanil hydrochloride (atovaquone/proguanil) is used for prevention of malaria caused by Plasmodium falciparum and for the treatment of acute, uncomplicated malaria caused by P. falciparum .1,5,6,7,8,9,10,13,14,115,134,143

Malaria

Prevention of Malaria

Atovaquone/proguanil is used in adults, adolescents, and children weighing 11 kg or more for prevention of malaria caused by P. falciparum (including chloroquine-resistant P. falciparum ).1,5,6,9,10,115,121,134

The risk of acquiring malaria varies substantially from traveler to traveler and from region to region (even within a single country) because of differences in the intensity of malaria transmission within the various regions and the 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 Although mosquito avoidance and protective measures against mosquito bites alone may be sufficient in areas where malaria occurs only sporadically and the risk for infection is considered low in travelers, malaria prevention in other areas involves chemoprophylaxis in addition to the usual mosquito avoidance and protective measures.115 Mosquito avoidance measures are important since no drug is 100% effective in preventing malaria.115,121 The choice of antimalarial for chemoprophylaxis depends on the traveler's risk of acquiring malaria in the area(s) visited, the risk of exposure to drug-resistant P. falciparum , other medical conditions (e.g., pregnancy), cost, and potential adverse effects.115,121,134

Although chloroquine has historically been considered the drug of choice for prevention of malaria in travelers to areas where chloroquine-resistant P. falciparum malaria has not been reported,121,134 chloroquine-resistant P. falciparum has now been confirmed in all areas with P. falciparum malaria, except the Caribbean, Central America west of the Panama Canal, and some countries in the Middle East.115 The US Centers for Disease Control and Prevention (CDC) and other experts state that options for prevention of malaria in travelers to malarious areas with chloroquine-susceptible P. falciparum include chloroquine (or hydroxychloroquine), atovaquone/proguanil, doxycycline, or mefloquine;115,121,134 primaquine phosphate may be an option in some cases (especially for travelers to areas with a high incidence of P. vivax malaria), provided the individual is not glucose-6-phosphate dehydrogenase (G-6-PD) deficient.115,121,134 Although travelers on long-term trips may prefer the convenience of the once-weekly regimen of chloroquine (or hydroxychloroquine), short-term travelers may prefer the shorter once-daily regimens of atovaquone/proguanil or primaquine.115 In addition, atovaquone/proguanil, doxycycline, or primaquine is a good choice for last-minute travelers since chemoprophylaxis with these drugs is started 1-2 days before travel whereas chloroquine, hydroxychloroquine, or mefloquine chemoprophylaxis must be started 1-2 weeks before travel.115

For prevention of malaria in individuals traveling to malarious areas where chloroquine-resistant P. falciparum has been reported, the CDC and other experts recommend atovaquone/proguanil, doxycycline, or mefloquine.115,121,134

Because atovaquone and proguanil are active only against the asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages), the fixed-combination preparation cannot prevent delayed primary attacks or relapse of P. ovale or P. vivax malaria and cannot provide a radical cure in malaria caused by these species.115 Therefore, terminal prophylaxis with a 14-day regimen of primaquine phosphate may be indicated in addition to atovaquone/proguanil prophylaxis if travelers were exposed in areas where P. ovale or P. vivax is endemic.115 (See Primaquine Phosphate 8:30.08.)

Travelers to countries with malaria should be instructed to seek prompt medical attention as soon as possible if they develop symptoms of malaria (e.g., fever with influenza-like symptoms such as chills, headache, myalgias, malaise) while traveling or after return (especially during the first 2 months).115,121 Malaria symptoms can develop as early as 7 days after initial exposure or can appear months after departure from a malarious area, after chemoprophylaxis is discontinued.115 Travelers should understand that malaria can be effectively treated early in the course of the disease, but that delays before initiation of therapy can have serious or even fatal consequences.115

Information on the risk of malaria transmission in specific countries, information on mosquito avoidance measures, recommendations regarding whether chemoprophylaxis of malaria is indicated, and information on the choice of antimalarials for prevention are available from the CDC at [Web] and [Web].115

Clinical Experience

Results of clinical studies of 10-12 weeks' duration indicate that atovaquone/proguanil provides essentially total (97-100% efficacy) protection against falciparum malaria in adults not previously exposed to infection with the parasite (nonimmune population)1,10 and in adults and children (4-16 years of age) previously exposed to the parasite (semi-immune population).1,5,6,9,10

Presumptive Self-treatment of Malaria

Travelers who elect not to take chemoprophylaxis for prevention of malaria and travelers who require or choose to use a prophylaxis regimen that may not have optimal efficacy (e.g., chloroquine prophylaxis in areas with chloroquine-resistant P. falciparum ) are at increased risk of acquiring malaria and may need prompt treatment.115 In addition, some travelers who are taking effective prophylaxis but who will be in very remote areas may decide, in consultation with their health-care provider, to take along an appropriate antimalarial that can be used for presumptive self-treatment if necessary.115,134

The antimalarial regimen provided for presumptive self-treatment should be different than the regimen that the traveler is using for prophylaxis.134 Travelers should be advised to initiate self-treatment promptly in the event of an influenza-like illness (e.g., fever, chills) if professional medical care is not readily available.115,134 Use of presumptive self-treatment is only a temporary measure and these travelers should be advised that it is imperative that they seek a professional medical evaluation as soon as possible.115

For presumptive self-treatment of malaria in travelers†, the CDC and other experts recommend atovaquone/proguanil or the fixed combination of artemether and lumefantrine (artemether/lumefantrine).115,134

Treatment of Uncomplicated Malaria

Atovaquone/proguanil is used in adults and children weighing 5 kg or more for the treatment of acute uncomplicated malaria caused by P. falciparum (including chloroquine-resistant P. falciparum ).1,7,8,13,14,134,143 The drug has been effective in regions where chloroquine, halofantrine (not commercially available in the US), mefloquine, or amodiaquine (not commercially available in the US) treatment is associated with substantial failure rates, presumably secondary to the prevalence of drug-resistant plasmodia.1

For the treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum or the treatment of uncomplicated malaria when the plasmodial species has not been identified, the CDC recommends atovaquone/proguanil, artemether/lumefantrine, or a regimen that includes quinine sulfate in conjunction with doxycycline, tetracycline, or clindamycin.143,144 Although mefloquine is another option for treatment in these patients,143,144 the CDC recommends that it be used only when other recommended treatment regimens cannot be used.143

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

For the treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax , the CDC recommends a regimen of quinine sulfate 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 Because quinine sulfate, doxycycline (or tetracycline), atovaquone/proguanil, and mefloquine are active only against asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages), a 14-day regimen of primaquine is indicated to prevent delayed primary attacks or relapse and provide a radical cure whenever any of these drugs is used for treatment of P. vivax or P. ovale malaria.143,144 (See Primaquine Phosphate 8:30.08.)

Pediatric patients with uncomplicated malaria generally can receive the same treatment regimens recommended for adults using age- and weight-appropriate drugs and dosages.143,144 For the treatment of uncomplicated chloroquine-resistant P. falciparum in children younger than 8 years of age, the CDC recommends atovaquone/proguanil or artemether/lumefantrine; mefloquine can be considered if no other options are available.144 For the treatment of chloroquine-resistant P. vivax malaria in children younger than 8 years of age, the CDC recommends mefloquine given in conjunction with primaquine.143,144 Alternatively, if mefloquine is 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

Pregnant women with uncomplicated malaria caused by P. malariae , P. vivax , P. ovale , or chloroquine-susceptible P. falciparum should receive prompt treatment with chloroquine (or hydroxychloroquine).143 The CDC recommends that pregnant women with uncomplicated malaria caused by chloroquine-resistant P. falciparum receive prompt treatment with either mefloquine or a regimen of quinine sulfate and clindamycin;143 mefloquine is recommended for those with uncomplicated malaria caused by chloroquine-resistant P. vivax .143 Alternatively, atovaquone/proguanil or artemether/lumefantrine can be considered for the treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum in pregnant women when other treatment options are not available or not tolerated and if potential benefits outweigh risks.143 (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

Patients with severe malaria require aggressive antimalarial treatment with a parenteral regimen of IV quinidine gluconate in conjunction with doxycycline, tetracycline, or clindamycin initiated as soon as possible after the diagnosis.143,144 (See Uses: Malaria, in Quinidine 24:04.04.04.)

Assistance with diagnosis or treatment of malaria is available by contacting 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

Clinical Experience

Results of clinical studies indicate that therapy with atovaquone/proguanil is more effective or as effective as therapy with other antimalarial agents.1,7,8,13,14 Response rates of 94-100% have been reported in clinical studies in adults and children 3 years of age or older with falciparum malaria;1,7,8,13,14 similar response rates were attained in study populations with a high incidence of HIV infection (e.g., Zambia).1 Atovaquone/proguanil is more effective than treatment with atovaquone alone (response rate: 66%) or proguanil alone (response rate: 6%).1,8 In these studies, atovaquone/proguanil was associated with parasite clearance within a median of 49-66.5 hours and resolution of fever within a median of 36-53.5 hours.7,13,14

Because falciparum malaria is the most prevalent form of malaria, data on efficacy of atovaquone/proguanil in nonfalciparum malaria are limited.1,8,143 Atovaquone/proguanil has been effective in a limited number of patients with malaria caused by P. vivax †, P. ovale †, or P. malariae †.1,8 Relapse occurred commonly in patients with P. vivax malaria,1,8 and additional therapy with primaquine phosphate is indicated to prevent relapse if atovaquone/proguanil is used for treatment of P. ovale or P. vivax malaria.1,3

Atovaquone and proguanil hydrochloride (atovaquone/proguanil) is administered orally with food or a milky drink.1

Atovaquone/proguanil usually is administered once daily as a single dose at the same time each day.1

If a patients vomits within 1 hour after receiving a dose of atovaquone/proguanil, another full dose should be administered as a replacement.1 Antiemetic agents may be used if necessary.1 (See Drug Interactions: Metoclopramide.)

Because of the bitter taste of proguanil, the manufacturer states that the commercially available atovaquone/proguanil tablets would not be palatable if chewed.17

For children who have difficulty swallowing tablets, atovaquone/proguanil tablets may be crushed and mixed with condensed milk just prior to administration.1 In one study, there was no change in the oral clearance of atovaquone or proguanil when the drugs were administered separately as crushed tablets mixed with milk or other liquids in children 3-5 years of age when compared with administration of whole tablets in older children.17 However, in this study, the commercially available, fixed combination of atovaquone and proguanil hydrochloride was not used.17

Dosage

Atovaquone/proguanil is commercially available as fixed-combination tablets (adult strength) containing 250 mg of atovaquone and 100 mg of proguanil hydrochloride and as fixed-combination pediatric tablets containing 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride.1

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

Dosage of atovaquone/proguanil in children is based on body weight.1

Prevention of Malaria

For prevention of malaria, atovaquone/proguanil prophylaxis should be initiated 1-2 days prior to entering the malarious area and continued during the stay and for 7 days after leaving the area.1,115,121,134

For prevention of malaria, the usual adult dosage of atovaquone/proguanil is 1 tablet (adult strength) once daily (250 mg of atovaquone and 100 mg of proguanil hydrochloride once daily).1,115,121,134

For prevention of malaria in children, dosage of atovaquone/proguanil is based on weight.1,115,121,134 (See Table 1.)

Although safety and efficacy of atovaquone/proguanil have not been established for prevention of malaria in pediatric patients weighing less than 11 kg,1 the US Centers for Disease Control and Prevention (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

Because atovaquone/proguanil cannot prevent delayed primary attacks or relapse of P. ovale or P. vivax malaria and cannot provide a radical cure in malaria caused by these species, terminal prophylaxis with a 14-day regimen of primaquine may also be indicated if exposure occurred in areas where P. ovale and P. vivax are endemic.115,134 Primaquine terminal prophylaxis generally is administered during the final 7 days of the atovaquone/proguanil regimen and then for an additional 7 days or, if that is not feasible, it should be given for 14 days after atovaquone/proguanil prophylaxis is discontinued.115 (See Primaquine Phosphate 8:30.08.)

Presumptive Self-treatment of Malaria

If atovaquone/proguanil is used for presumptive self-treatment of malaria† in travelers, the CDC and other experts recommend that adults receive 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).115,134

For presumptive self-treatment of malaria† in pediatric travelers, the CDC and other experts state that children weighing 5 kg or more may receive the usual pediatric dosage recommended for the treatment of uncomplicated malaria.115,134 (See Table 2.)

Travelers should be advised to keep an amount of atovaquone/proguanil sufficient for self-treatment in their possession during travel and to take it promptly in the event of a febrile illness if professional medical care is not readily available.115,134 Presumptive self-treatment of a possible malarial infection is only a temporary measure and it is imperative that a professional medical evaluation be obtained as soon as possible.115

Atovaquone/proguanil should not be used for self-treatment in individuals currently taking the drug for prevention of malaria.115,134

Treatment of Uncomplicated Malaria

For the treatment of acute, uncomplicated malaria caused by Plasmodium falciparum , the usual adult dosage of atovaquone/proguanil is 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 the incidence of nausea and vomiting, some clinicians suggest an alternative adult regimen of 2 tablets (adult strength) twice daily for 3 consecutive days.134

For the treatment of acute, uncomplicated malaria in children weighing 5 kg or more, dosage of atovaquone/proguanil is based on weight.1,121,134 (See Table 2.)

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

Special Populations

Renal Impairment

Dosage adjustments of atovaquone/proguanil are not needed in patients with mild to moderate renal impairment (creatinine clearance 30-80 mL/minute).1 The fixed combination should not be used for prophylaxis of malaria in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) and should be used with caution for treatment of malaria in such patients.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Hepatic Impairment

Dosage adjustments of atovaquone/proguanil are not needed in patients with mild to moderate hepatic impairment; data are not available regarding use of the fixed combination in patients with severe hepatic impairment.1 (See Hepatic Impairment under Cautions: Specific Populations.)

Contraindications

Atovaquone and proguanil hydrochloride (atovaquone/proguanil) is contraindicated in individuals with known hypersensitivity reactions (e.g., anaphylaxis, erythema multiforme, Stevens-Johnson syndrome, angioedema, vasculitis) to atovaquone, proguanil, or any ingredient in the formulation.1

Atovaquone/proguanil is contraindicated for prevention of malaria in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) because pancytopenia has been reported in patients with severe renal impairment receiving proguanil.1

Warnings/Precautions

Sensitivity Reactions

Allergic reactions, including anaphylaxis, angioedema, urticaria, and vasculitis have been reported in patients receiving atovaquone/proguanil.1 Photosensitivity, rash, erythema multiforme, and Stevens-Johnson syndrome also have been reported.1

For additional information on sensitivity reactions associated with atovaquone, see Cautions: Dermatologic and Sensitivity Reactions, in Atovaquone 8:30.92.1

GI Effects

Nausea, vomiting, or diarrhea occurred in 8-12% of adults receiving atovaquone/proguanil for the treatment of acute, uncomplicated malaria, and vomiting has been reported in up to 19% of children receiving the drug for treatment of malaria.1

Atovaquone absorption may be reduced in patients with vomiting or diarrhea. If atovaquone/proguanil is used in patients who are vomiting, parasitemia should be closely monitored and use of an antiemetic agent considered.1 Approximately 15% of adults receiving atovaquone/proguanil for the treatment of malaria in clinical studies received an antiemetic agent; response rates of 98% were reported in these patients.1 (See Drug Interactions: Metoclopramide.)

If severe or persistent vomiting or diarrhea occurs, alternative antimalarial therapy should be considered.1

Hepatotoxicity

Elevations in AST and ALT have occurred in patients receiving atovaquone/proguanil.1,8,13 In most patients, liver enzyme values returned to normal by day 28 of follow-up.8,13

Hepatitis and hepatic failure requiring liver transplantation have been reported in individuals receiving atovaquone/proguanil for prophylaxis of malaria.1

Malaria Recrudescence

Atovaquone/proguanil should not be used to treat recrudescence of malaria or malaria that occurs as a result of failure of treatment or chemoprophylaxis with the drug.1 A different antimalarial agent should be used.1

Selection and Use of Antimalarials

Oral antimalarials, including atovaquone/proguanil, should not be used for initial treatment of severe or complicated malaria.1,143 In the event of life-threatening, serious, or overwhelming malaria, aggressive treatment with a parenteral antimalarial regimen is necessary.143,144

Atovaquone/proguanil has not been 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 (See Users Guide.)

The manufacturer states that atovaquone/proguanil should be used in pregnant women only if potential benefits justify risks to the fetus.1

The US Centers for Disease Control and Prevention (CDC) states that use of atovaquone/proguanil in pregnant women may be considered for treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum when other treatment options are not available or not tolerated and if potential benefits outweigh risks.143 However, the CDC states that the drug should not be used for prevention of malaria in pregnant women.115

Lactation

Proguanil is distributed into human milk in small amounts; atovaquone is distributed into milk in rats.1,17

The manufacturer states that atovaquone/proguanil should be used with caution in nursing women.1

The CDC states that atovaquone/proguanil may be used for the 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 an area with multidrug-resistant malaria and other treatment options are not tolerated).115 However, the CDC states the drug should not be used for prevention of malaria in women breast-feeding infants who weigh less than 5 kg.115

Pediatric Use

Safety and efficacy of atovaquone/proguanil for prevention of malaria have not been established in children weighing less than 11 kg.1

Safety and efficacy of atovaquone/proguanil for treatment of malaria have not been established in children weighing less than 5 kg.1

Geriatric Use

Clinical studies did not include sufficient numbers of adults 65 years of age or older to determine whether response differs from younger adults; dosage should be selected with caution.1 The greater frequency of decreased hepatic, renal, and/or cardiac function, the higher systemic exposure to cycloguanil (active metabolite of proguanil), and the greater frequency of concomitant disease or drug therapy observed in geriatric individuals should be considered.1

Hepatic Impairment

Pharmacokinetics of atovaquone/proguanil have not been studied in patients with severe hepatic impairment.1,17

Renal Impairment

Proguanil and cycloguanil are excreted principally in urine.1 Atovaquone/proguanil is contraindicated for prevention of malaria in patients with severe renal impairment (creatinine clearance less than 30 mL/minute).1 The drug should be used with caution for treatment of malaria in patients with severe renal impairment and only if benefits of the 3-day treatment regimen outweigh the risks associated with increased drug concentrations.1

Common Adverse Effects

Adverse effects reported in 5% or more of patients receiving atovaquone/proguanil for the treatment of malaria include abdominal pain, nausea, vomiting, diarrhea, headache, asthenia, anorexia, dizziness, cough, dreams, oral ulcers, and pruritus.1 The lower dosage of atovaquone/proguanil used for prevention of malaria is better tolerated that the higher dosage used for the treatment of malaria.1

Drugs Affecting Hepatic Microsomal Enzymes

Proguanil is metabolized principally by cytochrome P-450 (CYP) 2C19 isoenzyme.1

Potential pharmacokinetic interactions with drugs that are CYP2C19 substrates or inhibitors.1

Antimycobacterial Agents

Concomitant use of atovaquone and proguanil hydrochloride (atovaquone/proguanil) and rifampin or rifabutin decreases atovaquone concentrations by approximately 50 and 34%, respectively.1

Concomitant use of atovaquone/proguanil and rifampin or rifabutin is not recommended.1

Antiretroviral Agents

Concomitant use of indinavir (800 mg 3 times daily for 14 days) and atovaquone (750 mg twice daily for 14 days) resulted in a 23% decrease in trough concentrations of indinavir, but did not affect peak plasma concentrations or the area under the plasma concentration-time curve (AUC) of indinavir.1

Indinavir and atovaquone/proguanil should be used concomitantly with caution.1

Metoclopramide

Concomitant use of metoclopramide and atovaquone decreases atovaquone bioavailability.1

Metoclopramide and atovaquone/proguanil should be used concomitantly only if other antiemetics are not available.1

Tetracycline

Concomitant use of tetracycline and atovaquone decreases plasma concentrations of atovaquone by approximately 40%.1

Patients receiving tetracycline and atovaquone/proguanil concomitantly should be closely monitored for parasitemia.1

Warfarin

Proguanil may potentiate the anticoagulant effects of warfarin.1

Caution is recommended when atovaquone/proguanil is initiated or discontinued in patients receiving warfarin and coagulation parameters should be monitored carefully.1

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 is 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

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 more than 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 is metabolized principally by CYP2C19 to the active metabolite cycloguanil and to 4-chlorophenylbiguanide.1

Elimination Route

Following oral administration in healthy individuals, more than 94% of a dose of atovaquone is excreted unchanged in feces and 40-60% of a dose of proguanil is 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, but 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

The pharmacokinetics of atovaquone and proguanil in patients with mild renal impairment (creatinine clearance 50-80 mL/minute) is similar to that in those with normal renal function.1 In patients with moderate renal impairment (creatinine clearance 30-50 mL/minute), oral clearance of atovaquone is unaffected but oral clearance of proguanil is reduced approximately 35%.1 In patients with severe renal impairment (creatinine clearance less than 30 mL/minute), peak plasma concentrations and AUC are reduced and elimination half-lives of both drugs are prolonged resulted 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

Description

Atovaquone and proguanil hydrochloride (atovaquone/proguanil) is a fixed combination of 2 antimalarial agents.1,3,4,5,6,7,8,9,10,13,14,15,134 Atovaquone, a hydroxynaphthoquinone derivative, is active against the erythrocytic stages of plasmodium development and is a blood schizonticidal agent;4,5 the drug also has activity against the early gametocyte stage.5 Proguanil, a biguanide derivative, is metabolized in vivo (principally by cytochrome P-450 [CYP] isoenzyme 2C19) to cycloguanil, an active metabolite.1,4,6,7 Proguanil and cycloguanil are active against erythrocytic and exoerythrocytic stages of plasmodium development; the drug is described as a slow blood schizonticidal agent.1,4,5 While atovaquone and proguanil are active against erythrocytic forms of most strains of Plasmodium falciparum , P. malariae , P. ovale , and P. vivax 1,8 and exoerythrocytic forms of Plasmodium spp.,1 neither drug has activity against P. vivax hypnozoites.3,8

Atovaquone and proguanil interfere with 2 different pathways involved in the biosynthesis of pyrimidines in the malarial parasite.1 In plasmodia, atovaquone selectively inhibits mitochondrial electron transport, reduces pyrimidine biosynthesis, and collapses mitochondrial membrane potential, thereby preventing parasite replication.1,5,6,7,8,10 In plasmodia, cycloguanil inhibits dihydrofolate reductase, leading to depletion of pyrimidine nucleotide pools and disruption in nucleic acid synthesis and cell replication.1,4,6,10 The antimalarial activity of atovaquone and proguanil is synergistic against erythrocytic stages of the parasite.5,6,7,13 While the mechanism of this synergistic activity has not been precisely determined, results from one study indicate that proguanil (rather than cycloguanil) lowers the concentration of atovaquone needed to collapse mitochondrial membrane potential in malarial parasites.15

Advice to Patients

Importance of taking atovaquone and proguanil (atovaquone/proguanil) at the same time each day with food or milk.

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

If a dose is missed, the missed dose should be taken as soon as it is remembered.1 If the dose is skipped, a double dose of atovaquone/proguanil should not be taken 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 informing clinicians of possible malaria exposure.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 concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1,115

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

Importance of discussing with clinician the risks and benefits of travel to malaria-endemic areas during pregnancy. 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.)

Additional Information

Overview^® (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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. [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. [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. [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. [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. [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. [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. [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. [PubMedCentral][PubMed 10348748]

16. Anon. The role of atovaquone and proguanil in control programmes. WHO Drug Information . 1999; 13:229.

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. [Web]

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. [Web]

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. [Web]

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. [Web]

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. [Web]