Atovaquone

Brand Names

• Malarone is a combination medication containing atovaquone and proguanil, used for both the prevention and treatment of malaria, including drug-resistant strains.

• Malarone Pediatric is a lower-dose formulation of the same combination, specifically designed for use in children.

• Malanil is an alternative brand name for the atovaquone/proguanil combination.

MECHANISM OF ACTION

Atovaquone works by disrupting the mitochondrial electron transport chain in parasites. It specifically inhibits the cytochrome bc1 complex through competitive binding, which results in the collapse of the mitochondrial membrane potential. This disruption indirectly halts the synthesis of pyrimidines—crucial building blocks needed for the parasite to replicate its DNA and RNA.

PHARMACOKINETICS:

Absorption

Atovaquone is a fat-soluble (lipophilic) medication with low and inconsistent absorption when taken by mouth. To improve its absorption and therapeutic effect, it should be taken with food—preferably a meal high in fat.

Distribution

Atovaquone binds extensively to plasma proteins (over 99.5%) but also distributes into body tissues, resulting in a large volume of distribution that tends to increase with a person’s body weight.

Metabolism

Atovaquone is minimally metabolized in the human body, with the majority of the drug being eliminated unchanged. This metabolic stability is a key feature of the drug, which was intentionally designed to resist breakdown by human liver enzymes.

Excretion

Atovaquone is minimally metabolized and is primarily excreted unchanged through the feces via biliary elimination. Negligible amounts of the drug are eliminated through the kidneys. 

PHARMACODYNAMICS

Atovaquone is a highly lipophilic compound that closely mimics the structure of ubiquinone. Due to this similarity, it exerts a comparable inhibitory effect by selectively disrupting mitochondrial electron transport, along with related processes such as ATP production and pyrimidine synthesis in parasites sensitive to atovaquone. In Plasmodium species, the cytochrome bc1 complex (complex III) appears to be a highly specific molecular target for the drug. Additionally, atovaquone does not carry a significant risk of myelosuppression, making it a favorable treatment option for patients undergoing bone marrow transplantation.

ADMINISTRATION

Atovaquone is an oral medication that comes as a liquid suspension or in tablets, and it must be taken with food to ensure proper absorption. It is available as a single drug (Mepron) or in combination with proguanil (Malarone). The specific administration instructions, dosage, and duration of treatment depend on the condition being treated and the specific formulation prescribed. 

DOSAGE AND STRENGTH

Atovaquone is an antimicrobial drug available as an oral suspension (Mepron) or in combination with proguanil in oral tablets (Malarone). Dosages and strengths vary based on the medication form and the condition being treated. 

• Oral suspension (Mepron): Contains 750 mg of atovaquone per 5 mL.

• Atovaquone/Proguanil tablets (Malarone and generics):

• Adult formulation: Each tablet contains 250 mg of atovaquone and 100 mg of proguanil hydrochloride.

• Pediatric formulation: Each tablet contains 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride.

DRUG INTERACTIONS

Atovaquone can interact with several other medications, including serious interactions with drugs such as rifampin, rifabutin, and warfarin. These interactions may either reduce atovaquone’s effectiveness or increase the likelihood of side effects. Additional important interactions include metoclopramide and tetracycline, both of which can lower atovaquone levels by interfering with its absorption. It is essential to inform your doctor about all medications you are taking to help prevent possible complications.

FOOD INTERACTIONS

Atovaquone has a notable interaction with food—its absorption is significantly enhanced when taken with a meal, especially one high in fat. Taking the medication on an empty stomach can result in low drug levels in the body, reducing its overall effectiveness.

CONTRAINDICATIONS
Atovaquone oral suspension is contraindicated in patients who develop or have a history of hypersensitivity reactions (e.g., angioedema, bronchospasm, throat tightness, urticaria) to atovaquone or any of the components of atovaquone oral suspension.

SIDE EFFECTS

• Persistent cough or hoarseness

• Difficulty breathing or shortness of breath

• Fever or chills

• Pain in the lower back or sides

• Painful or difficult urination

• Chest tightness

OVER DOSE

Overdoses of atovaquone alone, even large ones, do not have a well-defined set of severe symptoms, and overdoses of the combination drug atovaquone/proguanil are rarely life-threatening. Reported symptoms of atovaquone overdose include: 

• Rash

• Headache

• Tiredness

• Shortness of breath

• Grey-bluish color of the lips and/or skin

• Gastrointestinal upset (nausea, vomiting, diarrhea)

TOXICITY

Atovaquone is generally well-tolerated, but it can cause side effects ranging from common gastrointestinal issues to rare, more severe reactions. In most clinical applications, it is combined with proguanil, and the combined toxicity is often considered. Overdoses are typically managed with supportive care and generally do not result in permanent injury.