Atovaquone-Proguanil Hcl (atovaquone/proguanil HCl)

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

Dosage of atovaquone/proguanil is expressed in terms of the number of tablets (adult strength or pediatric) or as the dose of atovaquone and dose of proguanil hydrochloride.

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

The pharmacokinetics of atovaquone in individuals with renal or hepatic impairment and the possible need for caution and/or dosage adjustment remain to be fully determined. The manufacturer states that atovaquone should be used with caution and close monitoring in patients with severe hepatic impairment.

Atovaquone is administered orally.

Atovaquone must be taken with food to optimize GI absorption. (See Pharmacokinetics: Absorption.) Alternative therapy should be considered in patients who have difficulty taking atovaquone with food.

The multiple-dose bottle containing atovaquone oral suspension should be shaken gently before removing a dose.

If a single-dose foil pouch containing atovaquone oral suspension is used, the pouch should be opened by removing the perforated tab and the entire contents of the pouch ingested; the dose can be discharged from the pouch into a dosing spoon or cup or directly into the mouth.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antimalarial Agents/Penicillamine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use may result in additive or synergistic effects on the blood and kidneys(1) or increased penicillamine levels.(2)

CLINICAL EFFECTS: Concurrent use of penicillamine with antimalarials may result in serious hematologic or renal toxicity(1,2) or elevated levels of penicillamine.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of penicillamine states that penicillamine should not be used in patients receiving concurrent therapy with antimalarial agents.(1)

DISCUSSION: In patients with rheumatoid arthritis, concurrent chloroquine increased penicillamine plasma concentrations by 34% when compared to penicillamine alone.(2) In a 2-year controlled, double-blind trial of penicillamine, hydroxychloroquine, or combination therapy, patients on combination therapy did not do as well as patients receiving penicillamine alone.(3) Because antimalarial agents are associated with hematologic and renal toxicity, the manufacturer of penicillamine states that penicillamine should not be used in patients receiving concurrent antimalarials.(1)

Antimalarials/Artemether; Lumefantrine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Halofantrine and quinine may inhibit the metabolism of lumefantrine by CYP2D6.(1) The combination of artemether-lumefantrine and antimalarials may result in additive effects on the QT interval.(1)

CLINICAL EFFECTS: Concurrent use may result in toxicity and/or prolongation of the QT interval, which may result in life-threatening arrhythmias.(1,2)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The UK manufacturer of artemether-lumefantrine states that the concurrent use of artemether-lumefantrine with other antimalarials is contraindicated.(1) The US manufacturer of artemether-lumefantrine states that artemether-lumefantrine should not be given concurrently with antimalarials.(2) If a patient deteriorates during artemether-lumefantrine therapy and requires another antimalarial agent, it may be started immediately, but the UK manufacturer of artemether-lumefantrine recommends ECG and potassium monitoring.(1) In patients who have previously received halofantrine, both the UK and US manufacturers of artemether-lumefantrine recommends that one month elapse between the last dose of halofantrine and the initiation of artemether-lumefantrine.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in 14 healthy subjects, administration of a single intravenous dose of quinine (10 mg/kg) 2 hours after the sixth dose of artemether-lumefantrine had no effect on lumefantrine or dihydroartemisinin levels. Artemether levels were decreased; however, this was not believed to be clinically significant.(1,2) Concurrent quinine and artemether-lumefantrine produced a slight, but significant increase on the QTc interval.(1)

Atovaquone/Tetracycline

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: The concurrent administration of tetracycline may result in decreased levels and effectiveness of atovaquone.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The CDC states that tetracycline should not be administered with atovaquone.(1) If concurrent use of tetracycline and atovaquone is warranted, parasitemia should be closely monitored.(2)

DISCUSSION: Concurrent tetracycline has been associated with a 40% decrease in atovaquone plasma concentrations.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Atovaquone/Metoclopramide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Metoclopramide decreases the absorption of atovaquone.(1-3)

CLINICAL EFFECTS: The concurrent use of metoclopramide may result in decreased levels and effectiveness of atovaquone.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Metoclopramide should only be used in patients receiving atovaquone if no other antiemetic is available.(1-3)

DISCUSSION: Concurrent metoclopramide has been associated with a 50% decrease in atovaquone plasma concentrations.(1)

Atovaquone/Rifabutin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown but likely involves rifabutin-induced increase in the metabolism of atovaquone.(1,2)

CLINICAL EFFECTS: Concurrent administration of atovaquone with rifabutin may result in decreased levels and clinical effects of atovaquone(1,2).

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The administration of rifabutin during atovaquone therapy is not recommended.(1,2) Consider alternative agents to rifabutin during atovaquone therapy.(1) If coadministration is necessary, the National Institute of Health Opportunistic Infections guidelines recommend patients take atovaquone with a fatty meal and monitor for decreased atovaquone efficacy.(3)

DISCUSSION: In a study of 13 HIV-positive patients, rifampin (600 mg every 24 hours) and atovaquone (750 mg every 12 hours) resulted in a decrease in average atovaquone steady-state plasma concentration by 52% and an increase in average rifampin steady-state plasma concentration by 37%.(1) In a trial of 24 healthy volunteers, rifabutin 300 mg once daily with atovaquone oral suspension 750 mg twice daily resulted in a 34% decrease in the mean steady-state plasma atovaquone concentration and a 19% decrease in the mean steady-state plasma rifabutin concentration.(1)

Atovaquone/Rifampin; Rifapentine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.(1,2)

CLINICAL EFFECTS: Concurrent use may lead to decreased levels and clinical effects of atovaquone and increased levels of and side effects from the rifamycin.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concomitant administration with rifampin or rifapentine is not recommended by the US manufacturer of atovaquone and the National Institute of Health HIV guidelines.(1-3)

DISCUSSION: In a study of 13 HIV-positive patients, rifampin (600 mg every 24 hours) and atovaquone (750 mg every 12 hours) resulted in a decrease in average atovaquone steady-state plasma concentration by 52% and an increase in average rifampin steady-state plasma concentration by 37%.(1)

Atovaquone; Proguanil/Efavirenz

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism of interaction between atovaquone and efavirenz is unknown. Efavirenz, an inducer of CYP2C19, may induce the metabolism of proguanil.(1,2)

CLINICAL EFFECTS: Concurrent use of CYP2C19 inducers with atovaquone and proguanil may result in decreased levels and effectiveness of the antimalarial agents and treatment failure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concomitant administration of atovaquone/proguanil with efavirenz is not recommended and may result in decreased levels of atovaquone and proguanil.(1) Monitor patients for signs of treatment failure.

DISCUSSION: In a study of 30 human immunodeficiency virus (HIV)-infected subjects enrolled in three treatment arms (10 taking no antiretroviral therapy, 10 taking combination antiretroviral therapy including efavirenz, and 10 taking combination antiretroviral therapy with atazanavir/ritonavir) received atovaquone 750 mg BID for 14 days followed by atovaquone 1500 mg BID for 14 days, or vice-versa, with a washout period in between. The subjects on a combination antiretroviral regimen including efavirenz had a 47% and 44% lower atovaquone area-under-curve (AUC) on both dosing regimens, 750 mg BID and 1500 mg BID, respectively (p<0.01). Concentrations of atovaquone required to successfully treat Pneumocystis jiroveci pneumonia (average Concentration > 15 mcg/ml) were achieved in 50% of the subjects receiving an efavirenz based regimen. Concentrations of atovaquone required to successfully treat Toxoplasma encephalitis (average Concentration > 18.5 mcg/ml) were achieved in 20% of the subjects receiving an efavirenz based regimen with atovaquone 750 mg BID.(3) In a study of 76 HIV-infected patients, 18 healthy volunteers, 20 patients with efavirenz, 19 patients with lopinavir/ritonavir, or 19 patients with atazanavir/ritonavir received a single dose of atovaquone/proguanil 250/100 mg dose. The geometric mean ration (GMR) [95% confidence interval] AUC and maximum concentration (Cmax) for atovaquone, respectively, were 0.25 and 0.56 for patients on efavirenz, 0.26 and 0.56 for patients on lopinavir/ritonavir, and 0.54 and 0.51 for patients on atazanavir/ritonavir. Proguanil concentrations after adjustment for confounders including CYP2C19 genotype resulted in the GMR AUC of 0.57 for patients on efavirenz, 0.62 for patients on lopinavir/ritonavir, and 0.59 for patients on atazanavir/ritonavir. The Cmax for proguanil was unchanged in all three groups compared to healthy controls.(4)

There are no moderate interactions for this drug.

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

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

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min

• Disease of liver
• Malabsorption states

• Severe hepatic disease

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

Rare or Very Rare

• Abnormal hepatic function tests
• Anaphylaxis
• Angioedema
• Depression
• DRESS syndrome
• Erythema multiforme
• Hallucinations
• Hepatitis
• Hypersensitivity angiitis
• Nightmares
• Pancytopenia
• Panic disorder
• Psychiatric disorder
• Stevens-johnson syndrome
• Symptoms of anxiety
• Urticaria
• Vasculitis

More Frequent

• Abdominal pain with cramps
• Cough
• Diarrhea
• General weakness
• Headache disorder
• Myalgia
• Nausea
• Pruritus of skin
• Vomiting

Less Frequent

• Anorexia
• Aphthous stomatitis
• Dizziness
• Dyspepsia
• Gastritis
• Visual changes

Rare or Very Rare

• Back pain
• Fever
• Flu-like symptoms
• Insomnia
• Neutropenic disorder
• Skin photosensitivity
• Skin rash
• Stomatitis
• Upper respiratory infection

No enhanced messaging available.

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

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

Category C. (See Users Guide.)

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

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

Reproduction studies in rats using atovaquone dosages resulting in plasma concentrations up to 2-3 times the estimated human exposure have not revealed evidence of teratogenicity. However, maternal and fetal toxicity (decreased mean fetal body lengths and weights and increased early fetal resorption and postimplantation fetal loss) did occur in rabbits receiving oral atovaquone dosages resulting in plasma concentrations approximately one-half the estimated human exposure. It is not clear whether these effects were caused by atovaquone or resulted from maternal toxicity. Atovaquone concentrations in rabbit fetuses averaged 30% of concurrent maternal plasma concentrations. In another study, atovaquone concentrations in rat fetuses following single 14C-radiolabeled doses were 18% (middle gestation) and 60% (late gestation) of concurrent maternal plasma concentrations. There are no adequate and controlled studies to date using atovaquone in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

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

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

The CDC states that atovaquone/proguanil may be used for the treatment of malaria in women breast-feeding infants of any weight when potential benefits outweigh possible risks to the infant (e.g., when a breast-feeding woman has acquired P. falciparum malaria in an area with multidrug-resistant malaria and other treatment options are not tolerated). However, the CDC states the drug should not be used for prevention of malaria in women breast-feeding infants who weigh less than 5 kg.

It is not known whether atovaquone is distributed into human milk. The drug is distributed into breast milk of rats in concentrations 30% of concurrent maternal plasma concentrations. Atovaquone should be used with caution in nursing women.

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