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  • CLASSES

    Antimalarials

    DEA CLASS

    Rx

    DESCRIPTION

    Oral antimalarial combination with potent synergistic antimalarial activity. Atovaquone is structurally and pharmacologically related to the older antimalarials, lapinone and parvaquone. Proguanil is a synthetic biguanide derivative of pyrimidine and a prodrug for cycloguanil. Certain populations are poor metabolizers (e.g., Asian and African populations) of proguanil. In these patients, conversion of proguanil to cycloguanil is inadequate.

    COMMON BRAND NAMES

    Malarone, Malarone Pediatric

    HOW SUPPLIED

    Atovaquone, Proguanil/Atovaquone, Proguanil Hydrochloride/Malarone/Malarone Pediatric Oral Tab: 250-100mg, 62.5-25mg

    DOSAGE & INDICATIONS

    For the treatment of malaria.
    For the treatment of acute, uncomplicated malaria due to P. falciparum or P. vivax†.
    Oral dosage
    Adults

    4 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily for 3 consecutive days. Guidelines recommend for chloroquine-resistant infections and for infections of unknown resistance; may also use for chloroquine-sensitive infections if necessary. For P. vivax infections, add primaquine phosphate or tafenoquine. Not recommended in patients with previous prophylaxis with atovaquone; proguanil.[28387]

    Children and Adolescents weighing more than 40 kg

    4 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily for 3 consecutive days. Guidelines recommend for chloroquine-resistant infections and for infections of unknown resistance; may also use for chloroquine-sensitive infections if necessary. For P. vivax infections, add primaquine phosphate or tafenoquine (16 years and older). Not recommended in patients with previous prophylaxis with atovaquone; proguanil.[28387]

    Children and Adolescents weighing 31 to 40 kg

    3 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily for 3 consecutive days. Guidelines recommend for chloroquine-resistant infections and for infections of unknown resistance; may also use for chloroquine-sensitive infections if necessary. For P. vivax infections, add primaquine phosphate or tafenoquine (16 years and older). Not recommended in patients with previous prophylaxis with atovaquone; proguanil.[28387]

    Children weighing 21 to 30 kg

    2 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily for 3 consecutive days. Guidelines recommend for chloroquine-resistant infections and for infections of unknown resistance; may also use for chloroquine-sensitive infections if necessary. For P. vivax infections, add primaquine phosphate. Not recommended in patients with previous prophylaxis with atovaquone; proguanil.[28387]

    Infants and Children weighing 11 to 20 kg

    1 adult strength tablet (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily for 3 consecutive days. Guidelines recommend for chloroquine-resistant infections and for infections of unknown resistance; may also use for chloroquine-sensitive infections if necessary. For P. vivax infections, add primaquine phosphate. Not recommended in patients with previous prophylaxis with atovaquone; proguanil.[28387]

    Infants and Children weighing 9 to 10 kg

    3 pediatric strength tablets (62.5 mg atovaquone; 25 mg proguanil per tablet) PO once daily for 3 consecutive days. Guidelines recommend for chloroquine-resistant infections and for infections of unknown resistance; may also use for chloroquine-sensitive infections if necessary. For P. vivax infections, add primaquine phosphate. Not recommended in patients with previous prophylaxis with atovaquone; proguanil.[28387]

    Infants and Children weighing 5 to 8 kg

    2 pediatric strength tablets (62.5 mg atovaquone; 25 mg proguanil per tablet) PO once daily for 3 consecutive days. Guidelines recommend for chloroquine-resistant infections and for infections of unknown resistance; may also use for chloroquine-sensitive infections if necessary. For P. vivax infections, add primaquine phosphate. Not recommended in patients with previous prophylaxis with atovaquone; proguanil.[28387]

    For the treatment of severe malaria† prior to the availability of IV artesunate.
    Oral dosage
    Adults

    4 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once. Discontinue when IV artesunate therapy is started.

    Children and Adolescents weighing more than 40 kg

    4 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once. Discontinue when IV artesunate therapy is started.

    Children and Adolescents weighing 31 to 40 kg

    3 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once. Discontinue when IV artesunate therapy is started.

    Children weighing 21 to 30 kg

    2 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once. Discontinue when IV artesunate therapy is started.

    Infants and Children weighing 11 to 20 kg

    1 adult strength tablet (250 mg atovaquone; 100 mg proguanil per tablet) PO once. Discontinue when IV artesunate therapy is started.

    Infants and Children weighing 9 to 10 kg

    3 pediatric strength tablets (62.5 mg atovaquone; 25 mg proguanil per tablet) PO once. Discontinue when IV artesunate therapy is started.

    Infants and Children weighing 5 to 8 kg

    2 pediatric strength tablets (62.5 mg atovaquone; 25 mg proguanil per tablet) PO once. Discontinue when IV artesunate therapy is started.

    For the treatment of severe malaria† after IV artesunate therapy is completed.
    Oral dosage
    Adults

    4 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily for 3 consecutive days.

    Children and Adolescents weighing more than 40 kg

    4 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily for 3 consecutive days.

    Children and Adolescents weighing 31 to 40 kg

    3 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily for 3 consecutive days.

    Children weighing 21 to 30 kg

    2 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily for 3 consecutive days.

    Infants and Children weighing 11 to 20 kg

    1 adult strength tablet (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily for 3 consecutive days.

    Infants and Children weighing 9 to 10 kg

    3 pediatric strength tablets (62.5 mg atovaquone; 25 mg proguanil per tablet) PO once daily for 3 consecutive days.

    Infants and Children weighing 5 to 8 kg

    2 pediatric strength tablets (62.5 mg atovaquone; 25 mg proguanil per tablet) PO once daily for 3 consecutive days.

    For P. falciparum malaria prophylaxis, including in areas where chloroquine resistance has been reported.
    Oral dosage
    Adults

    1 adult strength tablet (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily. Begin 1 to 2 days before entering the endemic area; continue daily during the stay and for 7 days after leaving the area. Recommended for travel to all areas.

    Children and Adolescents weighing more than 40 kg

    1 adult strength tablet (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily. Begin 1 to 2 days before entering the endemic area; continue daily during the stay and for 7 days after leaving the area. Recommended for travel to all areas.

    Children and Adolescents weighing 31 to 40 kg

    3 pediatric tablets (62.5 mg atovaquone; 25 mg proguanil per tablet) PO once daily. Begin 1 to 2 days before entering the endemic area; continue daily during the stay and for 7 days after leaving the area. Recommended for travel to all areas.

    Children weighing 21 to 30 kg

    2 pediatric tablets (62.5 mg atovaquone; 25 mg proguanil per tablet) PO once daily. Begin 1 to 2 days before entering the endemic area; continue daily during the stay and for 7 days after leaving the area. Recommended for travel to all areas.

    Infants and Children weighing 11 to 20 kg

    1 pediatric tablet (62.5 mg atovaquone; 25 mg proguanil per tablet) PO once daily. Begin 1 to 2 days before entering the endemic area; continue daily during the stay and for 7 days after leaving the area. Recommended for travel to all areas.

    Infants and Children weighing 9 to 10 kg†

    Three-quarters pediatric tablet (62.5 mg atovaquone; 25 mg proguanil per tablet) PO once daily. Begin 1 to 2 days before entering the endemic area; continue daily during the stay and for 7 days after leaving the area. Recommended for travel to all areas.

    Infants and Children weighing 5 to 8 kg†

    One-half pediatric tablet (62.5 mg atovaquone; 25 mg proguanil per tablet) PO once daily. Begin 1 to 2 days before entering the endemic area; continue daily during the stay and for 7 days after leaving the area. Recommended for travel to all areas.

    For the treatment of refractory or relapsed babesiosis† as part of combination therapy.
    Oral dosage
    Adults

    4 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily has been used for malaria. Use in combination with azithromycin.

    Children and Adolescents weighing more than 40 kg

    4 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily has been used for malaria. Use in combination with azithromycin.

    Children and Adolescents weighing 31 to 40 kg

    3 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily has been used for malaria. Use in combination with azithromycin.

    Children weighing 21 to 30 kg

    2 adult strength tablets (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily has been used for malaria. Use in combination with azithromycin.

    Infants and Children weighing 11 to 20 kg

    1 adult strength tablet (250 mg atovaquone; 100 mg proguanil per tablet) PO once daily has been used for malaria. Use in combination with azithromycin.

    Infants and Children weighing 9 to 10 kg

    3 pediatric strength tablets (62.5 mg atovaquone; 25 mg proguanil per tablet) PO once daily has been used for malaria. Use in combination with azithromycin.

    Infants and Children weighing 5 to 8 kg

    2 pediatric strength tablets (62.5 mg atovaquone; 25 mg proguanil per tablet) PO once daily has been used for malaria. Use in combination with azithromycin.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Total of atovaquone 250 mg/100 mg (1 tablet) proguanil per day PO for prophylaxis; total of atovaquone 1 g/400 mg proguanil (4 tablets) per day PO for treatment (3 days only).

    Elderly

    Total of atovaquone 250 mg/100 mg (1 tablet) proguanil per day PO for prophylaxis; total of atovaquone 1 g/400 mg proguanil (4 tablets) per day PO for treatment (3 days only).

    Adolescents

    See weight-based dosing for each indication.

    Children

    See weight-based dosing for each indication.

    Infants

    >= 5 kg: See weight-based dosing for each indication.
    < 5 kg: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are necessary in patients with mild to moderate hepatic impairment (manufacturer data). Studies have not been conducted in patients with severe hepatic impairment.

    Renal Impairment

    CrCl > 30 mL/min: No dosage adjustment required.
    CrCl <= 30 mL/min: Atovaquone; proguanil should NOT be used for malaria prophylaxis. May use with caution for the active treatment of malaria only if the benefits of the 3-day treatment regimen outweigh the potential risks associated with increased drug exposure.

    ADMINISTRATION

    Oral Administration

    Atovaquone; proguanil should be administered with food or with milk or milk-based drink (i.e., nutritional supplement shake) to enhance oral absorption of atovaquone; food with high fat content is desired. Failure to administer the drug in this manner may limit treatment efficacy.
    Administer dose at the same time each day.
    Administer a repeat dose if vomiting occurs within 1 hour after dosing.

    Oral Solid Formulations

    The tablets may be crushed and mixed with condensed milk for children unable to swallow whole tablets.

    STORAGE

    Generic:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Malarone:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Malarone Pediatric:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Atovaquone; proguanil should not be administered to patients with known hypersensitivity to atovaquone or proguanil, or any component of the formulation. During clinical trials, rare cases of anaphylaxis following treatment with atovaquone; proguanil have been reported.

    Pulmonary edema, renal failure, renal impairment

    Atovaquone; proguanil is should be used cautiously, if at all, in patients with significant renal impairment or renal failure (creatinine clearance <= 30 mL/min). Atovaquone; proguanil should not be used for malaria prophylaxis in these patients. Renal impairment can enhance the hematologic adverse effects associated with proguanil and cycloguanil since both are primarily eliminated via the kidneys. Atovaquone; proguanil has not been evaluated for the treatment of cerebral malaria infection or other severe manifestations of complicated malaria infection including hyperparasitemia, pulmonary edema, or renal failure. Patients with severe malaria are not candidates for oral therapy.

    Diarrhea, GI disease, vomiting

    Patients with certain types of GI disease may have decreased atovaquone absorption. Atovaquone plasma concentrations have been associated with successful treatment outcomes. Any condition that impairs GI absorption of atovaquone, including failure to administer atovaquone with food, may thus limit treatment efficacy. Patients must take atovaquone with meals. Clinicians may need to consider alternative treatments to atovaquone for patients who have difficulty taking atovaquone with food. Absorption of atovaquone may also be reduced in patients with diarrhea or vomiting. If atovaquone; proguanil is used in patients who are vomiting, parasitemia should be closely monitored and the use of an antiemetic considered. Vomiting occurred in up to 19% of pediatric patients given treatment doses of atovaquone; proguanil. In controlled clinical trials, 15.3% of adults who were treated with atovaquone; proguanil received an antiemetic drug during that part of the trial when they received atovaquone; proguanil. Of these patients 98.3% were successfully treated. In patients with severe or persistent diarrhea or vomiting, alternative antimalarial therapy may be required.

    Pregnancy

    Guidelines do not recommend atovaquone; proguanil in pregnant women due to lack of data.[63990] Available data from published literature and postmarketing experience with atovaquone; proguanil during pregnancy are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Pregnant women with malaria are at increased risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth. Proguanil inhibits parasitic dihydrofolate reductase; continue folate supplementation in pregnant women and females of reproductive potential to prevent neural tube defects. Animal data suggest that the combination of atovaquone and proguanil is not associated with embryofetal developmental effects at doses up to 1.7 and 0.5 times, respectively, the estimated human exposure for the treatment of malaria. In animal studies, proguanil was not associated with fetal malformations but was associated with increased ureter variations when given during organogenesis to pregnant rats at a maternally toxic dose of 20 mg/kg/day corresponding to a plasma concentration of approximately 0.07 times the estimated human exposure for the treatment of malaria based on AUC. Atovaquone was not associated with fetal malformations when given during organogenesis to rats and rabbits at plasma exposures approximately 7 times the estimated human exposure for the treatment of malaria based on AUC.[28387]

    Breast-feeding

    There are no data on the presence of atovaquone in human milk; proguanil is present in human milk. Atovaquone is present in rat milk. There are no data on the effects of atovaquone; proguanil on the breast-fed infant or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for atovaquone; proguanil and any potential adverse effects on the breast-fed child from atovaquone; proguanil or the underlying maternal condition.[28387] Guidelines do not recommend atovaquone; proguanil for the prevention of malaria in a woman breast-feeding an infant weighing less than 5 kg unless the potential benefit outweighs the potential risk to the infant (such as treating a breast-feeding woman who has acquired P. falciparum malaria in an area of multidrug-resistant strains and who cannot tolerate other treatment options).[63990]

    Asian patients, Black patients, hepatic disease

    It is unknown if atovaquone; proguanil pharmacokinetics are altered in patients with hepatic disease. The effect of hepatic dysfunction on the conversion of proguanil to cycloguanil is also unknown. Caution is warranted in patients with hepatic function impairment. Twenty-percent of Black patients (e.g., native Kenyans) and 20% of Asian patients (e.g., Chinese, Japanese natives) are slow hepatic metabolizers of proguanil, which may impact treatment efficacy.

    Children, infants

    The safe and effective use of atovaquone; proguanil has not been established for the treatment of malaria in infants and children who weigh less than 5 kg and for prophylaxis of malaria in infants and children who weigh less than 11 kg.

    Geriatric

    Clinical studies of atovaquone; proguanil did not include sufficient numbers of geriatric adults aged 65 years and over to determine whether they respond differently from younger adults. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, the higher systemic exposure to cycloguanil, the active metabolite of proguanil, and the greater frequency of concomitant disease or other drug therapy.

    Driving or operating machinery

    Dizziness has been reported with atovaquone; proguanil therapy. Therefore, piloting aircraft, driving or operating machinery, or performing other hazardous tasks should be done cautiously until the effects of the drug are known.

    Sunlight (UV) exposure

    Photosensitivity has been reported with atovaquone; proguanil use. Patients should avoid excessive sunlight (UV) exposure and follow appropriate exposure precautions; therapy should be discontinued if phototoxicity occurs.

    ADVERSE REACTIONS

    Severe

    hepatic failure / Delayed / 0-1.0
    seizures / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    angioedema / Rapid / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    vasculitis / Delayed / 0-1.0
    pancytopenia / Delayed / 0-1.0

    Moderate

    elevated hepatic enzymes / Delayed / 16.9-26.7
    oral ulceration / Delayed / 2.0-9.0
    gastritis / Delayed / 2.0-3.0
    stomatitis / Delayed / 0-1.0
    hepatitis / Delayed / 0-1.0
    cholestasis / Delayed / 0-1.0
    hallucinations / Early / 0-1.0
    depression / Delayed / 0-1.0
    neutropenia / Delayed / 0-1.0
    anemia / Delayed / 0-1.0

    Mild

    diarrhea / Early / 1.0-38.0
    abdominal pain / Early / 2.0-33.0
    headache / Early / 10.0-22.0
    nausea / Early / 0-14.0
    vomiting / Early / 0-13.0
    myalgia / Early / 7.0-12.0
    cough / Delayed / 4.0-10.0
    fever / Early / 5.0-9.0
    influenza / Delayed / 2.0-9.0
    asthenia / Delayed / 8.0-8.0
    infection / Delayed / 0-8.0
    back pain / Delayed / 4.0-8.0
    dizziness / Early / 5.0-7.0
    pruritus / Rapid / 3.0-6.0
    anorexia / Delayed / 5.0-5.0
    insomnia / Early / 4.0-5.0
    dyspepsia / Early / 2.0-3.0
    anxiety / Delayed / 0-1.0
    photosensitivity / Delayed / 0-1.0
    rash / Early / 0-1.0
    urticaria / Rapid / 0-1.0

    DRUG INTERACTIONS

    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Atovaquone appears to increase the AUC of zidovudine by inhibiting the glucuronidation of zidovudine. Inhibition of zidovudine metabolism by atovaquone could result in an increase in zidovudine-induced adverse effects.
    Atazanavir: (Major) Concurrent administration of atazanavir plus ritonavir with atovaquone; proguanil has shown to decrease the atovaquone AUC by 46% and the proguanil AUC by 41%. Consider alternative malaria prophylaxis.
    Atazanavir; Cobicistat: (Major) Concurrent administration of atazanavir plus ritonavir with atovaquone; proguanil has shown to decrease the atovaquone AUC by 46% and the proguanil AUC by 41%. Consider alternative malaria prophylaxis.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of tetracycline can reduce the plasma concentrations of atovaquone by approximately 40%. Parasitemia should be closely monitored in patients receiving atovaquone and tetracycline.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of tetracycline can reduce the plasma concentrations of atovaquone by approximately 40%. Parasitemia should be closely monitored in patients receiving atovaquone and tetracycline.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Minor) The concurrent administration of ritonavir with atovaquone may result in decreased plasma levels of atovaquone. The clinical significance and mechanism of this potential interaction are unknown; the manufacturer states that an increase in atovaquone doses may be needed.
    Efavirenz: (Major) Avoid concurrent administration of efavirenz and atovaquone; proguanil. Use of these drugs together results in a 75% decreased in atovaquone AUC and a 43% decrease in proguanil AUC. Consider use of an alternative malaria prophylaxis.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid concurrent administration of efavirenz and atovaquone; proguanil. Use of these drugs together results in a 75% decreased in atovaquone AUC and a 43% decrease in proguanil AUC. Consider use of an alternative malaria prophylaxis.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent administration of efavirenz and atovaquone; proguanil. Use of these drugs together results in a 75% decreased in atovaquone AUC and a 43% decrease in proguanil AUC. Consider use of an alternative malaria prophylaxis.
    Esomeprazole: (Moderate) Esomeprazole may inhibit the CYP2C19 isoenzyme, leading to increased plasma levels of drugs that are substrates for the CYP2C19 isoenzyme, such as proguanil. Monitor the patient for common proguanil side effects, such as nausea or other stomach and intestinal complaints, headache, or increased hepatic enzymes when proguanil is given chronically.
    Fedratinib: (Moderate) Monitor for increased proguanil adverse reactions if administered with fedratinib. Proguanil is primarily metabolized by CYP2C19 and fedratinib is a moderate CYP2C19 inhibitor. Potential pharmacokinetic interactions between proguanil and CYP2C19 inhibitors are unknown.
    Indinavir: (Major) The use of atovaquone with food plus indinavir without food led to a decrease in the trough concentration of indinavir; changes in the AUC or maximum concentration of indinavir did not occur. Caution is advised if these drugs are coadministered.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) The administration of rifampin with atovaquone is not recommended, as rifampin is known to reduce atovaquone levels by 52%. In a small study of HIV-positive subjects, concomitant administration of oral rifampin with atovaquone suspension lead to a substantial decrease in average steady-state plasma atovaquone concentrations and a simultaneous increase in average steady-state plasma rifampin concentrations. The half-life of atovaquone decreased from 82 hours (without rifampin) to 50 hours during rifampin administration. Other rifamycins, (e.g.; rifapentine) may exert similar effects on atovaquone pharmacokinetics, but data are not available.
    Isoniazid, INH; Rifampin: (Major) The administration of rifampin with atovaquone is not recommended, as rifampin is known to reduce atovaquone levels by 52%. In a small study of HIV-positive subjects, concomitant administration of oral rifampin with atovaquone suspension lead to a substantial decrease in average steady-state plasma atovaquone concentrations and a simultaneous increase in average steady-state plasma rifampin concentrations. The half-life of atovaquone decreased from 82 hours (without rifampin) to 50 hours during rifampin administration. Other rifamycins, (e.g.; rifapentine) may exert similar effects on atovaquone pharmacokinetics, but data are not available.
    Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Atovaquone appears to increase the AUC of zidovudine by inhibiting the glucuronidation of zidovudine. Inhibition of zidovudine metabolism by atovaquone could result in an increase in zidovudine-induced adverse effects.
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of lopinavir; ritonavir with atovaquone; proguanil has shown to decrease the atovaquone AUC by 74% and the proguanil AUC by 38%. Consider alternative malaria prophylaxis or antiretroviral therapy. If used together, an increase in the atovaquone dose may be needed. The clinical significance and mechanism of this potential interaction are unknown. (Minor) The concurrent administration of ritonavir with atovaquone may result in decreased plasma levels of atovaquone. The clinical significance and mechanism of this potential interaction are unknown; the manufacturer states that an increase in atovaquone doses may be needed.
    Luliconazole: (Minor) Theoretically, luliconazole may increase the side effects of atovaquone; proguanil, as proguanil is a CYP2C19 substrate. Monitor patients for adverse effects of proguanil, such as GI and CNS effects. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP2C19 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
    Metoclopramide: (Major) Avoid the concomitant use of metoclopramide and atovaquone. Metoclopramide may reduce the bioavailability of atovaquone. Use metoclopramide with atovaquone only if other antiemetics are not available.
    Naproxen; Esomeprazole: (Moderate) Esomeprazole may inhibit the CYP2C19 isoenzyme, leading to increased plasma levels of drugs that are substrates for the CYP2C19 isoenzyme, such as proguanil. Monitor the patient for common proguanil side effects, such as nausea or other stomach and intestinal complaints, headache, or increased hepatic enzymes when proguanil is given chronically.
    Ombitasvir; Paritaprevir; Ritonavir: (Minor) The concurrent administration of ritonavir with atovaquone may result in decreased plasma levels of atovaquone. The clinical significance and mechanism of this potential interaction are unknown; the manufacturer states that an increase in atovaquone doses may be needed.
    Omeprazole; Amoxicillin; Rifabutin: (Major) The administration of rifabutin with atovaquone is not recommended. Taking these drugs together reduces the average steady-state plasma concentrations of atovaquone and rifabutin by 34% and 19%, respectively. Dose adjustments have not been established. If these drugs are given together, instruct patient to take atovaquone with a fatty meal and monitor for decreased atovaquone efficacy.
    Oritavancin: (Moderate) Proguanil is metabolized by CYP2C19; oritavancin is a weak CYP2C19 inhibitor. Coadministration may result in elevated proguanil plasma concentrations. If oritavancin and atovaquone; proguanil are administered concurrently, monitor patients for atovaquone; proguanil toxicity such as stomach pain, nausea, vomiting, or diarrhea.
    Penicillamine: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
    Phentermine; Topiramate: (Minor) Proguanil is metabolized to cycloguanil by CYP2C19. Potential interactions between proguanil or cycloguanil and other drugs that are CYP2C19 inhibitors are unknown. Use caution when combining atovaquone; proguanil with CYP2C19 inhibitors, such as topiramate.
    Rabies Vaccine: (Major) If administered concurrently, antimalarials can impair the immunologic response to the rabies vaccine, thereby, decreasing its protective effect. If possible, administration of antimalarials should be avoided during use of the rabies vaccine for postexposure prophylaxis. When antimalarials must be administered to persons also receiving the rabies vaccine for postexposure prophylaxis, a serum rabies antibody titer should be obtained on day 14 (day of the 4th vaccination) to ensure an acceptable antibody response has been induced.
    Rifabutin: (Major) The administration of rifabutin with atovaquone is not recommended. Taking these drugs together reduces the average steady-state plasma concentrations of atovaquone and rifabutin by 34% and 19%, respectively. Dose adjustments have not been established. If these drugs are given together, instruct patient to take atovaquone with a fatty meal and monitor for decreased atovaquone efficacy.
    Rifampin: (Major) The administration of rifampin with atovaquone is not recommended, as rifampin is known to reduce atovaquone levels by 52%. In a small study of HIV-positive subjects, concomitant administration of oral rifampin with atovaquone suspension lead to a substantial decrease in average steady-state plasma atovaquone concentrations and a simultaneous increase in average steady-state plasma rifampin concentrations. The half-life of atovaquone decreased from 82 hours (without rifampin) to 50 hours during rifampin administration. Other rifamycins, (e.g.; rifapentine) may exert similar effects on atovaquone pharmacokinetics, but data are not available.
    Rifapentine: (Moderate) The administration of rifampin with atovaquone is not recommended, as rifampin is known to reduce atovaquone levels by 52%. Rifapentine may exert similar effects on atovaquone pharmacokinetics, but data are not available. In a small study of HIV-positive subjects, concomitant administration of oral rifampin with atovaquone suspension lead to a substantial decrease in average steady-state plasma atovaquone concentrations and a simultaneous increase in average steady-state plasma rifampin concentrations. The half-life of atovaquone decreased from 82 hours (without rifampin) to 50 hours during rifampin administration.
    Ritonavir: (Minor) The concurrent administration of ritonavir with atovaquone may result in decreased plasma levels of atovaquone. The clinical significance and mechanism of this potential interaction are unknown; the manufacturer states that an increase in atovaquone doses may be needed.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Concomitant administration of atovaquone with an oral combination of trimethoprim and sulfamethoxazole lead to a minor decreases in TMP and SMX AUCs by 16% and 10%, respectively, in a small number of HIV-positive subjects. No difference was observed in atovaquone pharmacokinetics. The effect of the interaction of atovaquone with TMP-SMX is minor and unlikely to be of clinical significance. (Moderate) Concomitant administration of atovaquone with an oral combination of trimethoprim and sulfamethoxazole lead to a minor decreases in TMP and SMX AUCs in a small number of HIV-positive subjects. This may not be of any clinical significance but should be used with caution.
    Tetracycline: (Moderate) Concomitant use of tetracycline can reduce the plasma concentrations of atovaquone by approximately 40%. Parasitemia should be closely monitored in patients receiving atovaquone and tetracycline.
    Topiramate: (Minor) Proguanil is metabolized to cycloguanil by CYP2C19. Potential interactions between proguanil or cycloguanil and other drugs that are CYP2C19 inhibitors are unknown. Use caution when combining atovaquone; proguanil with CYP2C19 inhibitors, such as topiramate.
    Trimethoprim: (Moderate) Concomitant administration of atovaquone with an oral combination of trimethoprim and sulfamethoxazole lead to a minor decreases in TMP and SMX AUCs by 16% and 10%, respectively, in a small number of HIV-positive subjects. No difference was observed in atovaquone pharmacokinetics. The effect of the interaction of atovaquone with TMP-SMX is minor and unlikely to be of clinical significance.
    Typhoid Vaccine: (Major) If administered concurrently, atovaquone; proguanil can impair the immunologic response to the oral typhoid vaccine, thereby, decreasing its protective effect. If possible, administration of antimalarials should be avoided during use of the oral typhoid vaccine. In a study to determine the effects of antimalarials on the vaccine, thirty individuals were administered proguanil (200 mg daily) concurrently with the oral typhoid vaccine. Administration of proguanil with the vaccine significantly decreased the immune response to the vaccine; therefore, it is recommended to avoid administration of proguanil within 10 days of the final oral typhoid vaccine dose.
    Voriconazole: (Minor) Proguanil is metabolized to cycloguanil by CYP2C19. Use caution when combining atovaquone; proguanil with CYP2C19 inhibitors, such as voriconazole.
    Warfarin: (Moderate) The anticoagulant effects of warfarin and other coumarin-based anticoagulants may be increased when used concomitantly with proguanil; the mechanism of the interaction is not known. If proguanil is initiated in someone receiving warfarin, monitor the patient closely for an increased INR or symptoms of bleeding.
    Zidovudine, ZDV: (Minor) Atovaquone appears to increase the AUC of zidovudine by inhibiting the glucuronidation of zidovudine. Inhibition of zidovudine metabolism by atovaquone could result in an increase in zidovudine-induced adverse effects.

    PREGNANCY AND LACTATION

    Pregnancy

    Guidelines do not recommend atovaquone; proguanil in pregnant women due to lack of data.[63990] Available data from published literature and postmarketing experience with atovaquone; proguanil during pregnancy are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Pregnant women with malaria are at increased risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth. Proguanil inhibits parasitic dihydrofolate reductase; continue folate supplementation in pregnant women and females of reproductive potential to prevent neural tube defects. Animal data suggest that the combination of atovaquone and proguanil is not associated with embryofetal developmental effects at doses up to 1.7 and 0.5 times, respectively, the estimated human exposure for the treatment of malaria. In animal studies, proguanil was not associated with fetal malformations but was associated with increased ureter variations when given during organogenesis to pregnant rats at a maternally toxic dose of 20 mg/kg/day corresponding to a plasma concentration of approximately 0.07 times the estimated human exposure for the treatment of malaria based on AUC. Atovaquone was not associated with fetal malformations when given during organogenesis to rats and rabbits at plasma exposures approximately 7 times the estimated human exposure for the treatment of malaria based on AUC.[28387]

    There are no data on the presence of atovaquone in human milk; proguanil is present in human milk. Atovaquone is present in rat milk. There are no data on the effects of atovaquone; proguanil on the breast-fed infant or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for atovaquone; proguanil and any potential adverse effects on the breast-fed child from atovaquone; proguanil or the underlying maternal condition.[28387] Guidelines do not recommend atovaquone; proguanil for the prevention of malaria in a woman breast-feeding an infant weighing less than 5 kg unless the potential benefit outweighs the potential risk to the infant (such as treating a breast-feeding woman who has acquired P. falciparum malaria in an area of multidrug-resistant strains and who cannot tolerate other treatment options).[63990]

    MECHANISM OF ACTION

    The combination of atovaquone; proguanil has potent synergistic antimalarial activity; each agent acts by a different mechanism to combat malarial infections.
     
    •Atovaquone: Atovaquone acts against Plasmodia species by selectively interfering with mitochondrial processes such as mitochondrial electron transport and ATP and pyrimidine biosynthesis. Cytochrome bc1 complex (complex III) in Plasmodia appears to be a highly selective target for atovaquone. When administered alone, recrudescence has occurred due to atovaquone-resistant organisms several weeks after therapy was concluded. Atovaquone is also active against other protozoa including Pneumocystis carinii, Toxoplasma gondii, Entamoeba histolytica, Trichomonas vaginalis, Leishmania species, and microsporidia.
     
    •Proguanil: Proguanil is a slow-acting blood schizonticidal agent. It suppresses intraerythrocytic schizogony and has no effect on exoerythrocytic (intrahepatic) forms. The activity of proguanil is due to its active metabolite cycloguanil. Cycloguanil selectively inhibits the bifunctional dihydrofolate reductase-thymidylate synthetase enzyme of plasmodia. This results in inhibition of DNA synthesis and depletion of folate cofactors. Sporonticidal activity may also be present. Cycloguanil does not kill plasmodial gametocytes but it does impair development of fertilized gametes encysted in the gut of the mosquito thereby rendering the gametocyte noninfective to the mosquito.

    PHARMACOKINETICS

    Atovaquone; Proguanil is administered orally as a combination drug tablet.
    Atovaquone: Atovaquone is greater than 99% protein-bound; concentration in the CSF is less than 1% of the plasma concentration. Plasma concentrations do not increase proportionally with dose. There is indirect evidence of limited hepatic metabolism of atovaquone in humans, but no metabolites have been identified. Enterohepatic recirculation occurs; approximately 94% of an atovaquone dose is excreted in the feces unchanged. The mean half-life ranges 2 to 3 days in adult patients.
    Proguanil: Proguanil is approximately 75% bound to plasma proteins. Proguanil is metabolized to cycloguanil (active) primarily by cytochrome P450 2C19 and to 4-chlorophenyl-biguanide (inactive). This enzyme displays a known genetic polymorphism due to its deficiency in some sub-populations (e.g., 3% of White patients and about 20% of Asian and Kenyan patients are poor metabolizers). These patients may not achieve adequate plasma concentrations of the active compound cycloguanil. Approximately 40 to 60% of absorbed proguanil is excreted in the urine as unchanged drug or as cycloguanil. Fecal excretion accounts for about 10% of an administered dose. The elimination half-life of proguanil is 12 to 21 hours in adult patients. The elimination half-life may be longer in patients who are slow metabolizers.

    Oral Route

    Atovaquone: Atovaquone is lipophilic and hydrophobic resulting in poor and highly variable oral absorption; administration with a high-fat meal increases bioavailability significantly. The bioavailability of atovaquone as a single agent is roughly 23% with food; the combination product is thus recommended to be administered with food or a milky drink.
    Proguanil: Proguanil is adequately absorbed following oral administration regardless of food intake, however, absolute bioavailability data are lacking. Peak proguanil plasma concentrations (Cmax) occur within 5 hours (Tmax).