Professional Drug Information > Malarone

Atovaquone and Proguanil (Systemic)

VA CLASSIFICATION
Primary: AP101

Commonly used brand name(s): Malarone.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anti-protozoal—

Indications

General considerations
Atovaquone and proguanil metabolite, cycloguanil, are active against the erythrocytic and exoerythrocytic stages of Plasmodium species.^{01} The combination product has been shown to exert increased efficacy in the treatment of malaria in both immune and nonimmune patients compared with either agent alone.^{01}

Accepted

Malaria (prophylaxis and treatment)— Atovaquone and proguanil combination is indicated for the prevention of malaria caused by susceptible strains of P. falciparum in adults and children.^{01} This combination is also indicated for use in geographical regions that have previously shown chloroquine resistance.^{01}
—Atovaquone and proguanil combination is indicated for treatment of acute, uncomplicated malaria caused by susceptible strains of P. falciparum.^{01} It has been shown to be effective in geographical regions where resistance has diminished the efficacy of drugs such as amodiaquine, chloroquine, halofantrine, and mefloquine.^{01} However, atovaquone and proguanil combination may not be effective if malaria recurs following therapy.^{01}

Unaccepted
Safety and efficacy of atovaquone and proguanil combination have not been established for treatment of cerebral malaria or symptoms of severe, complicated malaria such as hyperparasitemia, pulmonary edema, or renal failure.^{01} Oral therapy is not recommended for treatment of such severe conditions.^{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Atovaquone: 366.84^{01}
    Proguanil: 290.22^{01}

Mechanism of action/Effect:

Atovaquone and proguanil interfere with two different pathways that are involved in the biosynthesis of pyrimidines required for parasitic nucleic acid replication.^{01}

Atovaquone selectivelyinhibits parasite mitochondrial electron transport.^{01}

Proguanil's primary mechanism is via its metabolite, cycloguanil. Dihydrofolate reductase is inhibited in the malaria parasite by cycloguanil and disrupts deoxythymidylate synthesis.^{01}

Absorption:

Atovaquone—Considerable variability among individuals. Because of its lipophilicity and low aqueous solubility, dietary fat intake increases absorption rate and extent; area under the plasma concentration–time curve (AUC) increases 2 to 3 times and C_max5 times over fasting.^{01}

Atovaquone Tablet—Total absolute bioavailability (taken with food): 23%^{01}

Proguanil—Extensive, regardless of food intake.^{01}


Distribution:

Atovaquone—Vol _D: 3.5 L per kg^{01}

Proguanil—Vol_D: 42 L per kg^{01}

Protein binding:

Atovaquone: Very high (99%)^{01}

Proguanil: High (75%)^{01}

Biotransformation:


Atovaquone:

Indirect evidence suggests that atovaquone undergoes limited metabolism.^{01} However, no metabolite has been identified.^{01}



Proguanil:

Metabolized into cycloguanil (via CYP2C19) and 4-chlorophenylbiguanide.^{01}


Half-life:

Atovaquone—Elimination: 2 to 3 days in adults; 1 to 2 days in children.^{01}

Proguanil— Elimination: 12 to 21 hours in adults and children; may be increased in patients who are slow metabolizers.^{01}

Elimination:


Atovaquone——
        Fecal: Greater than 94% was recovered unchanged over 21 days.^{01}
        Renal: Less than 0.6% was excreted in the urine.^{01}



Proguanil——
        Renal: Between 40 and 60%.^{01}



Precautions to Consider

Carcinogenicity/ Mutagenicity

Atovaquone: Carcinogenicity studies done in rats were negative. Studies done in mice showed treatment-related increases in hepatocellular adenomas and hepatocellular carcinomas at doses ranging 5 to 8 times the average steady-state plasma concentrations used in humans for prevention of malaria. ^{01} Atovaquone was found to be negative with or without metabolic activation in the Ames Salmonella mutagenicity assay, the mouse lymphoma mutagenesis assay, and the cultured human lymphocyte cytogenic assay. No evidence of genotoxicity was seen in the in vivo mouse micronucleus assay. ^{01}

Proguanil: Carcinogenicity studies have not been completed. It was not found to be genotoxic in either in vitro or in vivo studies. It was found to be negative or with out metabolic activation in the Ames Salmonella mutagenicity assay and the Mouse Lymphoma mutagenesis assay. There was no evidence of genotoxicity in the in vivo Mouse Micronucleus assay.^{01}

Atovaquone and proguanil: There have been no genotoxicity studies done. ^{01}

Pregnancy/Reproduction
Fertility—
Effects of atovaquone and proguanil combination on male and female reproductivity are unknown.^{01}

Pregnancy—

Note: Falciparum malaria carries a higher risk of morbidity and mortality in pregnant women. Maternal death and fetal loss are both known complications. Personal protection and antimalarials should always be used by pregnant women who must travel to malaria-endemic areas.^{01}
Although proguanil inhibits parasitic dihydrofolate reductase, there are no clinical data indicating that folate supplementation diminishes medication efficacy.^{01} It is not necessary for women of child-bearing age who are taking folate supplements to prevent neural tube defects to discontinue their use while taking atovaquone and proguanil combination.^{01}



Atovaquone: Not found to be teratogenic and did not cause reproductive toxicity in rats at maternal plasma concentrations up to 5 to 6.5 times the estimated human exposure. It did cause maternal toxicity in rabbits with plasma concentrations that were approximately 0.6 to 1.3 times the estimated human exposure. Decreased mean fetal body lengths, increased early resorption and post-implantation losses were found. It is not clear whether these effects were caused by atovaquone or were secondary to maternal toxicity. Concentrations in rabbit fetuses averaged 30% of the concurrent maternal plasma concentrations. After a single ¹⁴C-radiolabeled dose, concentrations of radiocarbon in rat fetuses were 18% (middle gestation) and 60% (late gestation) of concurrent maternal plasma concentrations. ^{01}

Atovaquone and proguanil: Not teratogenic in rats at plasma concentrations up to 1.7 and 0.1 times, respectively, the estimated human exposure during malaria treatment. In rabbits, it was not teratogenic or embryotoxic at concentrations up ot 0.34 and 0.82 times, respectively, the estimated human exposure during malaria treatment.^{01}

FDA Pregnancy Category C. ^{01}

Breast-feeding

Atovaquone: It is unknown whether atovaquone is distributed into human breast milk. However, a rat study showed concentrations were 30% of the concurrent atovaquone concentrations in maternal plasma.^{01}

Proguanil: Distributed into human breast milk in small quantities.^{01}

Atovaquone and proguanil: Caution should be used when prescribing to lactating women.^{01}

Pediatrics

There is no information on the relationship of age to the effects of atovaquone and proguanil in the pediatric population of patients who weigh less than 11 kg. Safety and efficacy have not been established in pediatrics weighing less than 11 kg. ^{01}


Geriatrics


Although appropriate studies on the relationship of age to the effects of atovaquone and proguanil combination have not been performed in the geriatric population, geriatrics-specific problems are not expected to limit the usefulness of atovaquone and proguanil in the elderly. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving this combination.^{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

» Metoclopramide    ( decreases bioavailability of atovaquone; use alternate antiemetics whenever possible^{01})


» Rifampin    (reduces atovaquone levels 50%; avoid concomitant use)

^{01}
» Proguanil-containing medications    (concomitant use should be avoided^{01})


» Tetracycline    (associated with approximately 40% reduction in plasma concentrations of atovaquone; closely monitor parasitemia in these patients)

^{01}

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT]) and     (values may be increased, and persist up to 4 weeks after treatment. ^{01})

^{01}
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to atovaquone, proguanil hydrochloride, or any component of the formulation. ^{01}
Risk-benefit should be considered when the following medical problems exist
» Diarrhea or vomiting    (absorption may be decreased; parasitemia should be monitored and antiemetic use considered; if severe or persistent then alternative malaria therapy should be considered)

^{01}
» Renal failure; severe, pre-existing    (due to drug elimination by renal excretion, caution should be used when prescribing)

^{01}
Recrudescent P. falciparum infections or failure of chemoprophylaxis    (treatment with a different blood schizonticide is recommended)

^{01}
Note: Relapse is common when treating P. vivax malaria




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal pain
^{01}    
asthenia (lack or loss of strength )
    
back pain
^{01}    
cough
^{01}    
diarrhea
^{01}    
headache ^{01}
    
myalgia (muscle pain)^{01}
    
nausea ^{01}
    
pruritus (itching skin)— pediatrics only
    
upper respiratory infection (cough ; fever; sneezing; sore throat)^{01}
    
vomiting ^{01}
{01}
Incidence less frequent
    
Anorexia (loss of appetite ; weight loss)
    
dizziness ^{01}
    
dyspepsia ( acid or sour stomach ; belching; heartburn; indigestion; stomach discomfort, upset, or pain)
^{01}    
fever ^{01}
    
flu syndrome ( chills; cough; diarrhea; fever ; general feeling of discomfort or illness ; headache ; joint pain ; loss of appetite ; muscle aches and pains ; nausea ; runny nose; shivering ; sore throat ; sweating ; trouble sleeping ; unusual tiredness or weakness; vomiting)^{01}
    
gastritis (burning feeling in chest or stomach ; indigestion ; stomach upset ; tenderness in stomach area)^{01}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of atovaquone and proguanil
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Note: There have been no known reports of overdosage of atovaquone and proguanil^{01}.


Note: The median lethal dose of atovaquone is higher than the mean oral dose tested in mice and rats (1825 mg per kg). Overdoses of up to 31,500 mg of atovaquone have been reported.^{01}


Note: Overdoses of 1500 mg of proquanil hydrochloride have been reported, followed by complete recovery, and doses as high as 700 mg twice daily have been taken over two weeks without serious toxicity. ^{01}

Atovaquone
    
Rash
^{01}
Proguanil
    
Aphthous ulceration, reversible (sores in mouth)
^{01}    
epigastric discomfort (pain in chest, upper stomach or throat; heartburn)
^{01}    
hair loss, reversible
^{01}    
hematologic side effects
^{01}    
scaling of the skin on palms or soles
^{01}    
vomiting ^{01}


Treatment of overdose
There is no known antidote for atovaquone, and it is unknown if it is dialyzable.^{01}

Treatment is primarily symptomatic and supportive.

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Atovaquone and Proguanil (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to atovaquone, proguanil hydrochloride, or any component of the formulation. ^{01}





Breast-feeding—It is not known if atovaquone is distributed into breast milk Proguanil is distributed into breast milk in small quantities. Caution should be used when administering to lactating women,^{01}
Other medications, especially metoclopramide, proguanil hydrochloride containing drugs, rifampin and tetracycline.^{01}
Other medical problems, especially diarrhea or vomiting; recrudescent P. falciparum infections or failure of chemoprophylaxis; or severe, preexisting renal failure

Proper use of this medication
Taking medication at the same time each day

» Taking with food or a milky drink
^{01}
» Repeating dose if vomiting occurs within 1 hour^{01}

» Proper dosing
Taking as soon as possible; contacting doctor for further instructions.

Proper storage

Precautions while using this medication

Personal protection measures to prevent malaria, such as:
Remaining in air-conditioned or well-screened rooms to reduce human-mosquito contact

Sleeping under mosquito netting; preferably impregnated with permethrin-containing insecticide

Wearing suitable clothing (long-sleeved shirt or long trousers) to protect arms and legs when mosquitos are out

Applying mosquito repellents containing N,N–diethyl-m-toluamide (DEET) to uncovered areas of skin when mosquitos are out

Using a pyrethrum-containing flying insect spray to kill mosquitos


General Dosing Information
Prophylactic treatment should start 1 to 2 days before entering the malaria-endemic area. It should be continued daily and extend until 7 days after return from the region.^{01}

The dose of atovaquone and proguanil combination should be repeated if vomiting occurs within 1 hour after administration.^{01}

Parasite relapse commonly occurred with P. vivax malaria, when it was treated with atovaquone and proguanil alone.^{01}

Diet/Nutrition
Diet/Nutrition

Atovaquone and proguanil combination should be taken at the same time each day with food or a milky drink.^{01}


Oral Dosage Forms

ATOVAQUONE AND PROGUANIL HYDROCHLORIDE TABLETS

Usual Adult Dose
Malaria (prophylaxis)
Oral, 250 mg atovaquone and 100 mg proguanil (one adult strength tablet) per day, beginning 1–2 days prior to entering an endemic area and continuing daily until 7 days after return.^{01}

Malaria (treatment)
Oral, 1 gram atovaquone and 400 mg proguanil (4 adult strength tablets) as a single dose daily for three consecutive days.^{01}


Usual Pediatric Dose
Malaria (prophylaxis)
Oral, pediatric strength tablets, dose is based on body weight and is started 1–2 days prior to entrance into endemic area and continuing daily until 7 days after return.^{01}

11-20 kg: 62.5 mg atovaquone and 25 mg proguanil (1 pediatric strength tablet) daily.^{01}

21-30 kg: 125 mg atovaquone and 50 mg proguanil (2 pediatric strength tablets) as a single dose daily.^{01}

31-40 kg: 187.5 mg atovaquone and 75 mg proguanil (3 pediatric strength tablets) as a single dose daily.^{01}

greater than 40 kg: 250 mg atovaquone and 100 mg proguanil (1 adult strength tablet) as a single dose daily.^{01}.

Malaria (treatment)
Oral, dose is based on body weight.^{01}

11-20 kg: 250 mg atovaquone and 100 mg proguanil (1 adult strength tablet) daily for 3 consecutive days.^{01}

21-30 kg: 500 mg atovaquone and 200 mg proguanil (2 adult strength tablets) as a single dose daily for 3 consecutive days.^{01}

31-40 kg: 750 mg atovaquone and 300 mg proguanil (3 adult strength tablets) as a single dose daily for 3 consecutive days.^{01}

greater than 40 kg: 1 gram atovaquone and 400 mg proguanil (4 adult strength tablets) as a single dose daily for 3 consecutive days.^{01}


Usual Geriatric Dose
See Usual adult dose.

Note: Caution should be exercised when this medication is used in geriatric patients because of the potential for age-related renal function impairment.^{01}


Strength(s) usually available
U.S.—


250 mg atovaquone, 100 mg proguanil hydrochloride (Rx) [Malarone (low-substituted hydroxypropyl cellulose ) ( magnesium stearate) ( microcrystalline cellulose) ( poloxamer 188) (povidone K30) (and sodium starch glycolate )]^{01}


62.5 mg atovaquone, 25 mg proguanil hydrochloride (Rx) [Malarone (low-substituted hydroxypropyl cellulose) ( magnesium stearate) (microcrystalline cellulose ) (poloxamer 188) (povidone K30) ( sodium starch glycolate )]^{01}

Packaging and storage:
Store at 25 °C (77 °F), excursions permitted to 15° to 30 ° (59° to 86°).^{01}

Auxiliary labeling:
   • Take with food or milk.

Developed: 11/03/2000

References

1. Product Information: Malarone ™, atovaquone and proguanil. Glaxo Wellcome, Research Triangle Park, NC, (PI issued 07/2000) reviewed 10/2000.
   

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