ATOVAQUONE AND PROGUANIL HYDROCHLORIDE
Clinical safety rating: safe
Metoclopramide and rifampin reduce plasma concentrations Should not be used for serious Pneumocystis pneumonia (PCP) in patients who cannot take it with food.
Atovaquone is a mitochondrial electron transport inhibitor that selectively targets the cytochrome bc1 complex, disrupting pyrimidine synthesis in Plasmodium. Proguanil hydrochloride is a prodrug converted to cycloguanil, which inhibits dihydrofolate reductase (DHFR), blocking DNA synthesis. The combination synergistically inhibits plasmodial replication.
| Metabolism | Atovaquone: hepatic metabolism (glucuronidation), minimal CYP involvement; Proguanil: metabolized by CYP2C19 to active metabolite cycloguanil. |
| Excretion | Atovaquone: >94% excreted unchanged in feces via biliary elimination; renal excretion minimal (<1%). Proguanil: ~40-60% excreted renally as unchanged drug and metabolites (primarily cycloguanil and 4-chlorophenylbiguanide). |
| Half-life | Atovaquone: terminal half-life 2-3 days (67-83 hours); prolonged to 4-5 days in malaria due to drug accumulation. Proguanil: terminal half-life 12-21 hours; cycloguanil 14-21 hours. |
| Protein binding | Atovaquone: >99.9% bound to albumin. Proguanil: 75% bound to serum proteins (albumin and alpha-1-acid glycoprotein). |
| Volume of Distribution | Atovaquone: Vd 3.0 L/kg (extensive tissue distribution). Proguanil: Vd 15-25 L/kg (large distribution, accumulates in erythrocytes). |
| Bioavailability | Atovaquone: oral bioavailability 23-47% (variable, increased to ~50% with high-fat meal). Proguanil: ~100% oral bioavailability; cycloguanil bioavailability 30-40%. |
| Onset of Action | Oral: Antimalarial effect begins within 24-48 hours against susceptible Plasmodium falciparum; maximal parasite clearance in 72-96 hours. |
| Duration of Action | Atovaquone/proguanil provides chemoprophylaxis for up to 1 week after last dose (due to long half-life); treatment duration is 3 days for acute malaria. Clinical cure achieved within 3 days of therapy. |
250 mg atovaquone/100 mg proguanil hydrochloride (1 tablet) orally once daily for prophylaxis; 4 tablets (1000 mg/400 mg) orally once daily for 3 consecutive days for treatment.
| Dosage form | TABLET |
| Renal impairment | For prophylaxis: CrCl 30-50 mL/min: reduce dose to 1 tablet every other day; CrCl <30 mL/min: not recommended. For treatment: CrCl <30 mL/min: not recommended. |
| Liver impairment | No dose adjustment required for mild to moderate hepatic impairment; not studied in severe hepatic impairment (Child-Pugh class C). |
| Pediatric use | Prophylaxis (weight-based): 11-20 kg: 62.5 mg/25 mg (1/4 adult tablet) daily; 21-30 kg: 125 mg/50 mg (1/2 tablet) daily; 31-40 kg: 187.5 mg/75 mg (3/4 tablet) daily; >40 kg: adult dose. Treatment (weight-based): 11-20 kg: 2 tablets (500 mg/200 mg) once daily for 3 days; 21-30 kg: 3 tablets (750 mg/300 mg); 31-40 kg: 4 tablets (1000 mg/400 mg); >40 kg: adult dose. |
| Geriatric use | No specific dose adjustment; use with caution due to age-related decline in renal function; monitor renal function and adjust according to renal impairment guidelines. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Metoclopramide and rifampin reduce plasma concentrations Should not be used for serious Pneumocystis pneumonia (PCP) in patients who cannot take it with food.
| FDA category | Animal |
| Breastfeeding | Atovaquone and proguanil are excreted into human milk in small amounts. The milk-to-plasma ratio (M/P) for atovaquone is 0.3; for proguanil, approximately 1.2. The American Academy of Pediatrics considers compatible with breastfeeding. However, caution in infants with G6PD deficiency due to potential hemolysis from proguanil. Monitor infant for diarrhea, rash, or hemolytic anemia. |
| Teratogenic Risk |
■ FDA Black Box Warning
No FDA black box warning.
| Common Effects | Rash |
| Serious Effects |
["Known hypersensitivity to atovaquone or proguanil","Severe renal impairment (CrCl <30 mL/min) for prophylaxis","Not recommended for treatment of severe malaria"]
| Precautions | ["May cause severe or fatal hepatotoxicity, including hepatic failure and elevation of liver enzymes","Patients with severe renal impairment (CrCl <30 mL/min) should not use for prophylaxis; use with caution for treatment","Monitoring for parasitemia and clinical response required in patients with vomiting or diarrhea due to reduced absorption","Should not be used for severe malaria or malaria complicated by other organ dysfunction"] |
| Food/Dietary | Take with fatty food or whole milk to increase absorption. Avoid concurrent use with tetracycline, metoclopramide, or rifampin (decrease atovaquone levels). Grapefruit juice may increase proguanil levels; avoid excessive consumption. |
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| Pregnancy Category C. In animal studies, atovaquone was not teratogenic in rats or rabbits at doses up to 1.4 and 3 times the human dose based on AUC, respectively. Proguanil hydrochloride was not teratogenic in rats at doses up to 30 mg/kg/day (approximately 1.5 times human dose) but associated with maternal toxicity and reduced fetal weight. No adequate human studies; however, data from inadvertent exposure during clinical trials suggest no increased risk of major malformations. Use only if benefit outweighs risk. First trimester: limited data, theoretical risk of antifolate effects from proguanil; second and third trimesters: consider malaria risk vs. unknown fetal risk. |
| Fetal Monitoring | Monitor liver function tests (LFTs) and renal function at baseline and periodically. Complete blood count (CBC) to detect anemia or neutropenia. In pregnancy, monitor fetal growth via ultrasound if prolonged treatment. Assess for signs of malaria (fever, chills) as drug may mask symptoms. |
| Fertility Effects | No human studies on fertility. In animal studies, atovaquone and proguanil showed no adverse effects on fertility or reproductive performance. Theoretical concern: antifolate effect of proguanil could impact spermatogenesis or oogenesis, but no data. |
| Clinical Pearls | Administer with fatty food or whole milk to enhance absorption of atovaquone. Prophylaxis should start 1-2 days before travel and continue for 7 days after leaving endemic area. Not recommended for severe malaria (high parasite burden) due to slower parasite clearance. Caution in severe renal impairment (CrCl <30 mL/min) as proguanil accumulates. Monitor for hepatotoxicity and GI intolerance. |
| Patient Advice | Take with a fatty meal or whole milk each time to ensure the medication works properly. · Complete the full course of treatment even if you feel better. · Use effective contraception during treatment and for 2 months after the last dose if female of childbearing potential. · Report any signs of liver problems: yellowing of skin/eyes, dark urine, or severe nausea/vomiting. · Do not use for severe malaria or if you are unable to tolerate oral medications. · Start prophylaxis 1-2 days before travel and continue for 7 days after returning. |