Atovaquone; proguanil is an oral antimalarial combination. Plasmodium falciparum exhibits a high incidence of resistance to both atovaquone and proguanil as single agents for the treatment of malaria. The combination, however, has potent synergistic antimalarial activity. Atovaquone is structurally and pharmacologically related to older antimalarials, lapinone and parvaquone. Proguanil is a synthetic biguanide derivative of pyrimidine and is actually a prodrug for the active drug cycloguanil. In certain populations which are poor metabolizers (e.g., Asian and African populations), the conversion of proguanil to cycloguanil is inadequate and therapeutic concentrations of the active compound are not achieved. Malarone(R) was approved by FDA July 14, 2000 for the prevention and treatment of malaria.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific 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.
This monograph discusses the use of the combination atovaquone and proguanil. Clinicians may wish to consult the individual atovaquone monograph for more information.
Gastrointestinal adverse events associated with the use of atovaquone; proguanil during clinical trials include abdominal pain (2-33%), nausea (<= 14%), vomiting (<= 13%), diarrhea (1-38%), anorexia (5%), dyspepsia (2-3%), gastritis (2-3%), and oral ulceration (2-9%). Stomatitis was noted in post-marketing reports.
Elevated hepatic enzymes (AST, ALT) were reported in 16.9-26.7% of patients. during studies of atovaquone; proguanil and were noted to persist up to 4 weeks after discontinuation of treatment. Rare cases of hepatitis, cholestasis, and one report of fatal hepatic failure have been reported in patients taking atovaquone.
Nervous system and psychiatric adverse events associated with atovaquone; proguanil include headache (10-22%), asthenia (8%), dizziness (5-7%), abnormal/vivid dreams (2-7%), insomnia (4-5%), visual difficulties (2-3%), depression (< 1%), and anxiety (< 1%). Rare cases of seizures and psychotic events such as hallucinations have been noted in post-marketing reports.
Pruritus was reported in 3-6% of patients during atovaquone; proguanil trials. Allergic reactions such as angioedema, urticaria, and rare cases of anaphylactoid reactions and vasculitis were noted in post-marketing reports. Other post-marketing adverse events include photosensitivity, rash (unspecified), and rare cases or erythema multiforme and Stevens-Johnson syndrome.
General or infectious adverse events reported during atovaquone; proguanil clinical trials include fever (5-9%), cough (4-10%), upper respiratory tract infection (<= 8%), and influenza syndrome (2-9%).
Myalgia (7-12%) and back pain (4-8%) were reported during trials with atovaquone; proguanil.
In post-marketing reports with atovaquone; proguanil, neutropenia and rarely anemia occurred. Pancytopenia was noted in patients with severe renal impairment treated with proguanil.
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.
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.
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.
Guidelines do not recommend atovaquone; proguanil in pregnant women due to lack of data. 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.
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. 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).
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.
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.
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.
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.
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.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Plasmodium falciparum, Plasmodium sp.
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
This drug may also have activity against the following microorganisms: Babesia microti
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.
For the treatment of malaria:
-for the treatment of acute, uncomplicated malaria due to P. falciparum, P. vivax*, P. ovale*, P. malariae*, or P. knowlesi*:
Oral dosage:
Adults: 1,000 mg atovaquone; 400 mg proguanil 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 or P. ovale infections, add primaquine phosphate. Not recommended in patients with previous prophylaxis with atovaquone; proguanil.
Children and Adolescents weighing more than 40 kg: 1,000 mg atovaquone; 400 mg proguanil 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 or P. ovale infections, add primaquine phosphate. Not recommended in patients with previous prophylaxis with atovaquone; proguanil.
Children and Adolescents weighing 31 to 40 kg: 750 mg atovaquone; 300 mg proguanil 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 or P. ovale infections, add primaquine phosphate. Not recommended in patients with previous prophylaxis with atovaquone; proguanil.
Children weighing 21 to 30 kg: 500 mg atovaquone; 200 mg proguanil 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 or P. ovale infections, add primaquine phosphate. Not recommended in patients with previous prophylaxis with atovaquone; proguanil.
Infants and Children weighing 11 to 20 kg: 250 mg atovaquone; 100 mg proguanil 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 or P. ovale infections, add primaquine phosphate. Not recommended in patients with previous prophylaxis with atovaquone; proguanil.
Infants and Children weighing 9 to 10 kg: 187.5 mg atovaquone; 75 mg proguanil 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 or P. ovale infections, add primaquine phosphate. Not recommended in patients with previous prophylaxis with atovaquone; proguanil.
Infants and Children weighing 5 to 8 kg: 125 mg atovaquone; 50 mg proguanil 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 or P. ovale infections, add primaquine phosphate. Not recommended in patients with previous prophylaxis with atovaquone; proguanil.
-for the treatment of severe malaria* prior to the availability of IV artesunate:
Oral dosage:
Adults: 1,000 mg atovaquone; 400 mg proguanil PO once. Discontinue when IV artesunate therapy is started.
Children and Adolescents weighing more than 40 kg: 1,000 mg atovaquone; 400 mg proguanil PO once. Discontinue when IV artesunate therapy is started.
Children and Adolescents weighing 31 to 40 kg: 750 mg atovaquone; 300 mg proguanil PO once. Discontinue when IV artesunate therapy is started.
Children weighing 21 to 30 kg: 500 mg atovaquone; 200 mg proguanil PO once. Discontinue when IV artesunate therapy is started.
Infants and Children weighing 11 to 20 kg: 250 mg atovaquone; 100 mg proguanil PO once. Discontinue when IV artesunate therapy is started.
Infants and Children weighing 9 to 10 kg: 187.5 mg atovaquone; 75 mg proguanil PO once. Discontinue when IV artesunate therapy is started.
Infants and Children weighing 5 to 8 kg: 125 mg atovaquone; 50 mg proguanil PO once. Discontinue when IV artesunate therapy is started.
-for the treatment of severe malaria* after IV artesunate therapy is completed:
Oral dosage:
Adults: 1,000 mg atovaquone; 400 mg proguanil PO once daily for 3 consecutive days.
Children and Adolescents weighing more than 40 kg: 1,000 mg atovaquone; 400 mg proguanil PO once daily for 3 consecutive days.
Children and Adolescents weighing 31 to 40 kg: 750 mg atovaquone; 300 mg proguanil PO once daily for 3 consecutive days.
Children weighing 21 to 30 kg: 500 mg atovaquone; 200 mg proguanil PO once daily for 3 consecutive days.
Infants and Children weighing 11 to 30 kg: 250 mg atovaquone; 100 mg proguanil PO once daily for 3 consecutive days.
Infants and Children weighing 9 to 10 kg: 187.5 mg atovaquone; 75 mg proguanil PO once daily for 3 consecutive days.
Infants and Children weighing 5 to 8 kg: 125 mg atovaquone; 50 mg proguanil PO once daily for 3 consecutive days.
For malaria prophylaxis:
Oral dosage:
Adults: 250 mg atovaquone; 100 mg proguanil PO once daily, starting 1 to 2 days prior to entry into endemic area and continuing for 7 days after leaving the area. Recommended for travel to all areas.
Children and Adolescents weighing more than 40 kg: 250 mg atovaquone; 100 mg proguanil PO once daily, starting 1 to 2 days prior to entry into endemic area and continuing for 7 days after leaving the area. Recommended for travel to all areas.
Children and Adolescents weighing 31 to 40 kg: 187.5 mg atovaquone; 75 mg proguanil PO once daily, starting 1 to 2 days prior to entry into endemic area and continuing for 7 days after leaving the area. Recommended for travel to all areas.
Children weighing 21 to 30 kg: 125 mg atovaquone; 50 mg proguanil PO once daily, starting 1 to 2 days prior to entry into endemic area and continuing for 7 days after leaving the area. Recommended for travel to all areas.
Infants and Children weighing 11 to 20 kg: 62.5 mg atovaquone; 25 mg proguanil PO once daily, starting 1 to 2 days prior to entry into endemic area and continuing for 7 days after leaving the area. Recommended for travel to all areas.
Infants and Children weighing 9 to 10 kg*: 46.875 mg atovaquone; 18.75 mg proguanil (three-fourths of a pediatric tablet) PO once daily, starting 1 to 2 days prior to entry into endemic area and continuing for 7 days after leaving the area. Recommended for travel to all areas.
Infants and Children weighing 5 to 8 kg*: 31.25 mg atovaquone; 12.5 mg proguanil (one-half of a pediatric tablet) PO once daily, starting 1 to 2 days prior to entry into endemic area and continuing 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.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
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.
Patients with Renal Impairment Dosing
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.
*non-FDA-approved indication
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.
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 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.
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.
Nirmatrelvir; 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.
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.
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.
-Route-Specific Pharmacokinetics
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).
-Special Populations
Hepatic Impairment
-Atovaquone: In subjects with mild or moderate hepatic impairment as compared to healthy subjects, there were no marked differences in the rate or extent of systemic exposure of atovaquone. The elimination half-life is increased in patients with moderate hepatic impairment.
-Proguanil: Patients with mild to moderate hepatic impairment have an increase in proguanil systemic exposure (AUC), Cmax, and half-life which correspond to marked decreases in cycloguanil AUC and Cmax and to increases in the half-life of cycloguanil. Few measurable cycloguanil serum concentrations are observed in patients with moderate hepatic impairment. The pharmacokinetics of atovaquone, proguanil, and cycloguanil have not been studied in patients with severe hepatic impairment.
Renal Impairment
Compared to patients with normal renal function (CrCl greater than 80 mL/min), patients with mild renal impairment (CrCl 50 to 80 mL/min) have similar pharmacokinetic parameters for atovaquone; proguanil. No data exist regarding long term prophylaxis (greater than 2 months) in patients with moderate renal failure.
-Atovaquone: The oral clearance of atovaquone is comparable for patients with normal renal function and patients with mild renal impairment. In patients with severe renal impairment (CrCl less than 30 mL/min), atovaquone AUC and Cmax are reduced.
-Proguanil: In patients with moderate renal impairment (CrCl 30 to 50 mL/min), the mean oral clearance for proguanil is reduced by approximately 35% compared with patients with normal renal function. In patients with severe renal impairment (CrCl less than 30 mL/min), the elimination half-lives of proguanil and cycloguanil are prolonged; the corresponding AUC is increased, resulting in potential drug accumulation and toxicity with repeated dosing.
Pediatrics
-Atovaquone: Pharmacokinetic parameters in pediatric patients are similar to those in adults, however, the elimination half-life is 1 to 2 days in pediatric patients.
-Proguanil: The elimination half-life of proguanil is 12 to 21 hours in pediatric patients.
Geriatric
Elderly patients (65 to 79 years) have an increased cycloguanil (main metabolite of proguanil) AUC, and longer Tmax and elimination half-life compared to younger adults (30 to 45 years).
Ethnic Differences
Proguanil is metabolized to the active compound cycloguanil (primarily by the cytochrome P450 isoenzyme CYP2C19) 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 and the elimination half-life may be longer in patients who are slow metabolizers.