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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 acute, uncomplicated malaria due to P. falciparum or P. vivax†.
    Oral dosage
    Adults, Adolescents, and Children weighing more than 40 kg

    4 adult strength tablets (250 mg atovaquone/100 mg proguanil per tablet) PO once daily as a single dose for 3 consecutive days. The CDC recommends for chloroquine-resistant infections and for infections of unknown resistance; may also be used for chloroquine-sensitive infections if necessary. May be used as oral-step down therapy after IV quinidine for severe disease. For P. vivax infections, add primaquine phosphate. If a full treatment course has been administered without clinical cure, alternative treatment should be given. Similarly, if previous prophylaxis with atovaquone; proguanil has failed, do not use for curative treatment. Atovaquone; proguanil has been shown effective in regions where the drugs chloroquine, halofantrine, mefloquine, and amodiaquine may have unacceptable failure rates, presumably due to drug resistance.

    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. The CDC recommends for chloroquine-resistant infections and for infections of unknown resistance; may also be used for chloroquine-sensitive infections if necessary. May be used as oral-step down therapy after IV quinidine for severe disease. For P. vivax infections, add primaquine phosphate. If a full treatment course has been administered without clinical cure, alternative treatment should be given. Similarly, if previous prophylaxis with atovaquone; proguanil has failed, do not use for curative treatment. Atovaquone; proguanil has been shown effective in regions where the drugs chloroquine, halofantrine, mefloquine, and amodiaquine may have unacceptable failure rates, presumably due to drug resistance.

    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. The CDC recommends for chloroquine-resistant infections and for infections of unknown resistance; may also be used for chloroquine-sensitive infections if necessary. May be used as oral-step down therapy after IV quinidine for severe disease. For P. vivax infections, add primaquine phosphate. If a full treatment course has been administered without clinical cure, alternative treatment should be given. Similarly, if previous prophylaxis with atovaquone; proguanil has failed, do not use for curative treatment. Atovaquone; proguanil has been shown effective in regions where the drugs chloroquine, halofantrine, mefloquine, and amodiaquine may have unacceptable failure rates, presumably due to drug resistance.

    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. The CDC recommends for chloroquine-resistant infections and for infections of unknown resistance; may also be used for chloroquine-sensitive infections if necessary. May be used as oral-step down therapy after IV quinidine for severe disease. For P. vivax infections, add primaquine phosphate. If a full treatment course has been administered without clinical cure, alternative treatment should be given. Similarly, if previous prophylaxis with atovaquone; proguanil has failed, do not use for curative treatment. Atovaquone; proguanil has been shown effective in regions where the drugs chloroquine, halofantrine, mefloquine, and amodiaquine may have unacceptable failure rates, presumably due to drug resistance.

    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. The CDC recommends for chloroquine-resistant infections and for infections of unknown resistance; may also be used for chloroquine-sensitive infections if necessary. May be used as oral-step down therapy after IV quinidine for severe disease. For P. vivax infections, add primaquine phosphate. If a full treatment course has been administered without clinical cure, alternative treatment should be given. Similarly, if previous prophylaxis with atovaquone; proguanil has failed, do not use for curative treatment. Atovaquone; proguanil has been shown effective in regions where the drugs chloroquine, halofantrine, mefloquine, and amodiaquine may have unacceptable failure rates, presumably due to drug resistance.

    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. The CDC recommends for chloroquine-resistant infections and for infections of unknown resistance; may also be used for chloroquine-sensitive infections if necessary. May be used as oral-step down therapy after IV quinidine for severe disease. For P. vivax infections, add primaquine phosphate. If a full treatment course has been administered without clinical cure, alternative treatment should be given. Similarly, if previous prophylaxis with atovaquone; proguanil has failed, do not use for curative treatment. Atovaquone; proguanil has been shown effective in regions where the drugs chloroquine, halofantrine, mefloquine, and amodiaquine may have unacceptable failure rates, presumably due to drug resistance.

    For P. falciparum malaria prophylaxis, including in areas where chloroquine resistance has been reported.
    Oral dosage
    Adults, Adolescents, and Children weighing more than 40 kg

    1 adult strength tablet (250 mg atovaquone/100 mg proguanil per tablet) PO once daily. Begin prophylaxis 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 areas with endemic chloroquine-sensitive or resistant malaria and mefloquine-resistant malaria.

    Children and Adolescents weighing 31 to 40 kg

    3 pediatric tablets (62.5 mg atovaquone/25 mg proguanil per tablet) PO once daily. Begin prophylaxis 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 areas with endemic chloroquine-sensitive or resistant malaria and mefloquine-resistant malaria.

    Children weighing 21 to 30 kg

    2 pediatric tablets (62.5 mg atovaquone/25 mg proguanil per tablet) PO once daily. Begin prophylaxis 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 areas with endemic chloroquine-sensitive or resistant malaria and mefloquine-resistant malaria.

    Infants and Children weighing 11 to 20 kg

    1 pediatric tablet (62.5 mg atovaquone/25 mg proguanil per tablet) PO once daily. Begin prophylaxis 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 areas with endemic chloroquine-sensitive or resistant malaria and mefloquine-resistant malaria.

    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 prophylaxis 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 areas with endemic chloroquine-sensitive or resistant malaria and mefloquine-resistant malaria.

    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 prophylaxis 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 areas with endemic chloroquine-sensitive or resistant malaria and mefloquine-resistant malaria.

    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

    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

    Atovaquone; proguanil is classified as FDA pregnancy risk category C. Animal data suggest that the combination does not cause teratogenic or embryotoxic effects. However, cycloguanil, the active metabolite of proguanil, has had positive results in mouse tests for mutagenesis; these positive results were significantly reduced or eliminated with folinic acid (leucovorin) supplementation. No adequate or well-controlled pregnancy studies have been done in humans. Use in pregnancy only if the potential benefits of treatment outweigh the potential risks to the fetus. Proguanil and cycloguanil inhibit parasitic dihydrofolate reductase, however, there are no clinical data indicating that folate supplementation diminishes drug efficacy. Folate supplementation to prevent neural tube birth defects may be continued while taking atovaquone; proguanil. Pregnant women should avoid traveling to areas where chloroquine-resistant Plasmodium falciparum is endemic. Pregnant women who contract malaria have a higher mortality rate and greater morbidity compared to other adults, however, the risks of malaria during pregnancy may far outweigh any harmful effects due to antimalarial drug therapy. Genotoxicity studies have not been performed with atovaquone; proguanil. The effects of atovaquone on male and female reproductive performance are unknown.

    Breast-feeding

    It is not known if atovaquone is excreted into breast milk. Proguanil is excreted in human milk in small quantities. The manufacturer recommends that caution should be exercised when atovaquone; proguanil is administered to a woman who is breast feeding. However, dosage has been established for pediatric patients weighing as little as 5 kg, so it is unlikely to adversely affect a breast-fed infant weighing 5 kg or more. The Centers for Disease control and Prevention (CDC) does not currently recommend it for the prevention of malaria in women breast-feeding an infant weighing less than 5 kg. However, it can be used to treat women who are breast-feeding an infant of any weight when 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). In general, very small amounts of antimalarial drugs are excreted in the breast milk of lactating women. Because the quantity of antimalarial drugs transferred in breast milk is insufficient to provide adequate protection against malaria, an infant who requires chemoprophylaxis must receive the recommended dosages of antimalarial drugs. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    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 (unspecified) / 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.
    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.
    Esomeprazole; Naproxen: (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.
    Etoposide, VP-16: (Minor) Concurrent administration of atovaquone with etoposide may result in increased serum concentrations of etoposide. Caution is recommended during concurrent use due to the increased risk of etoposide-related effects including myelosuppression, secondary malignancy. Separation of the administration times by 1 to 2 days may prevent this interaction, although this is still to be proven.
    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 or rifabutin with atovaquone is not recommended, as these drugs are known to reduce atovaquone levels by roughly 50% and 34%, respectively. 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 or rifabutin with atovaquone is not recommended, as these drugs are known to reduce atovaquone levels by roughly 50% and 34%, respectively. 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: (Minor) 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. (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.
    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.
    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: (Severe) Antimalarials have adverse reactions similar to those of penicillamine. Concomitant use is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
    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.
    Rifampin: (Major) The administration of rifampin or rifabutin with atovaquone is not recommended, as these drugs are known to reduce atovaquone levels by roughly 50% and 34%, respectively. 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 or rifabutin with atovaquone is not recommended, as these drugs are known to reduce atovaquone levels by roughly 50% and 34%, respectively. 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

    Atovaquone; proguanil is classified as FDA pregnancy risk category C. Animal data suggest that the combination does not cause teratogenic or embryotoxic effects. However, cycloguanil, the active metabolite of proguanil, has had positive results in mouse tests for mutagenesis; these positive results were significantly reduced or eliminated with folinic acid (leucovorin) supplementation. No adequate or well-controlled pregnancy studies have been done in humans. Use in pregnancy only if the potential benefits of treatment outweigh the potential risks to the fetus. Proguanil and cycloguanil inhibit parasitic dihydrofolate reductase, however, there are no clinical data indicating that folate supplementation diminishes drug efficacy. Folate supplementation to prevent neural tube birth defects may be continued while taking atovaquone; proguanil. Pregnant women should avoid traveling to areas where chloroquine-resistant Plasmodium falciparum is endemic. Pregnant women who contract malaria have a higher mortality rate and greater morbidity compared to other adults, however, the risks of malaria during pregnancy may far outweigh any harmful effects due to antimalarial drug therapy. Genotoxicity studies have not been performed with atovaquone; proguanil. The effects of atovaquone on male and female reproductive performance are unknown.

    It is not known if atovaquone is excreted into breast milk. Proguanil is excreted in human milk in small quantities. The manufacturer recommends that caution should be exercised when atovaquone; proguanil is administered to a woman who is breast feeding. However, dosage has been established for pediatric patients weighing as little as 5 kg, so it is unlikely to adversely affect a breast-fed infant weighing 5 kg or more. The Centers for Disease control and Prevention (CDC) does not currently recommend it for the prevention of malaria in women breast-feeding an infant weighing less than 5 kg. However, it can be used to treat women who are breast-feeding an infant of any weight when 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). In general, very small amounts of antimalarial drugs are excreted in the breast milk of lactating women. Because the quantity of antimalarial drugs transferred in breast milk is insufficient to provide adequate protection against malaria, an infant who requires chemoprophylaxis must receive the recommended dosages of antimalarial drugs. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    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 > 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—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 Caucasians and about 20% of Asians and Kenyans are poor metabolizers). These patients may not achieve adequate plasma concentrations of the active compound cycloguanil. Approximately 40—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).