Atovaquone and Proguanil Hydrochloride - Mechanism of Action, Indications, Dosage, and Adverse Drug Reactions

Overview

Atovaquone and Proguanil hydrochloride tablets treat and prevent malaria (a parasite-borne illness). They prevent parasites from proliferating within red blood cells. Adults and children should take one dose daily before visiting malaria-infected areas and continue for seven days after returning. The combination of Atovaquone and Proguanil hydrochloride was approved by the Food and Drug Administration (FDA) on July 14, 2000.

Drug Group

Together, proguanil hydrochloride and Atovaquone are classified as antimalarial medications. These drugs function by eradicating malaria-causing microorganisms. Antimalarial drugs are used to treat and prevent malaria, a parasite-borne illness.

Indications

• Prevention of Malaria: To prevent Plasmodium falciparum malaria, a combination of Atovaquone and Proguanil hydrochloride is recommended, even in regions where reports of Chloroquine resistance have been made.

• Malaria Treatment: Acute, uncomplicated P. falciparum malaria is approved for treatment with Atovaquone and Proguanil hydrochloride combinations. In areas where drug resistance is likely to cause unacceptable failure rates for medications, including Amodiaquine, Mefloquine, Chloroquine, and Halofantrine, the Atovaquone and Proguanil hydrochloride combination has demonstrated efficacy.

What Are the Contraindications?

• When individuals have a history of known hypersensitivity (exaggerated immune response) responses (such as anaphylaxis (severe allergic reaction), erythema multiforme (skin hypersensitivity reaction), Stevens-Johnson syndrome (severe skin reaction), angioedema (swelling under the skin), or vasculitis (blood vessel inflammation)) to Atovaquone, Proguanil hydrochloride, or any other ingredient in the formulation, Atovaquone and Proguanil hydrochloride combination should not be administered.

• Atovaquone and Proguanil hydrochloride combination should not be used to prevent P. falciparum malaria in those who have significant pancytopenia (low blood cell count)-related renal impairment (creatinine clearance less than 30 mL/min (milliliters per minute)) in individuals receiving Proguanil treatment for severe renal failure.

Dosage Forms and Available Strengths

The Atovaquone and Proguanil hydrochloride combination tablet, an adult-strength medication, contains 100 mg (milligrams) of Proguanil hydrochloride and 250 mg of Atovaquone. A pediatric tablet has 25 mg of Proguanil hydrochloride and 62.5 mg of Atovaquone.

Warnings and Precautions

• Patients with diarrhea or vomiting may experience decreased Atovaquone absorption, necessitating careful monitoring of parasitemia (parasites in the blood) when administering antiemetics. Severe or prolonged diarrhea or vomiting may necessitate the use of an alternate antimalarial medication.

• In patients treated with Atovaquone and Proguanil hydrochloride combination alone for mixed P. falciparum and Plasmodium vivax infections, P. vivax relapsed often.

• Patients should be treated with a different blood schizonticide (an agent that selectively destroys the schizont of a sporozoan parasite) if they experience recurrent P. falciparum infections following treatment or if prophylaxis is unsuccessful.

• Prophylactic use has been associated with elevated liver laboratory tests, instances of hepatitis (liver inflammation), and hepatic failure necessitating liver transplantation.

• The efficacy of the Atovaquone and Proguanil hydrochloride combination in treating cerebral malaria or other severe forms of complicated malaria has not been studied. Oral treatment is not appropriate for individuals with severe malaria.

For Patients

What Is Malaria?

Plasmodium parasites, which cause malaria, are a potentially fatal disease humans contract through female Anopheles mosquitoes carrying the infection. Fever, headache, and chills are among the symptoms; severe symptoms include acute exhaustion, disorientation, convulsions, breathing difficulties, dark or bloody urine, jaundice (yellowish discoloration of the skin and sclera due to excess bilirubin), and irregular bleeding.

People with HIV (human immunodeficiency virus) or AIDS (acquired immunodeficiency syndrome), pregnant women, children under five, infants, and travelers are more likely to get a serious infection. The three main ways that malaria is transmitted are by mosquito bites, infected needles, and blood transfusions. Five different species of Plasmodium parasites cause human malaria, the two most deadly of which are P. vivax, which is common outside of sub-Saharan Africa, and P. falciparum, which is common in Africa.

How Does the Atovaquone and Proguanil Hydrochloride Combination Work?

The Atovaquone and Proguanil hydrochloride combination is an effective malaria treatment that prevents the parasite from growing and reproducing in the human body. By impairing the parasite's mitochondrial activity, Atovaquone disrupts its energy metabolism, leading to its death. Proguanil inhibits the enzyme dihydrofolate reductase, which is essential for DNA (deoxyribonucleic acid) production. This combination affects the erythrocytic and exoerythrocytic stages of the parasite's life cycle, but its effectiveness may vary depending on malaria resistance.

What Are the Benefits of the Atovaquone and Proguanil Hydrochloride Combination?

• Effectiveness: Artesunate-Mefloquine and Atovaquone-Proguanil are equally efficacious in treating uncomplicated Plasmodium falciparum malaria. When traveling to malaria areas, individuals from non-malaria areas frequently take them to prevent malaria.

• Dual Action: The combination influences the malaria parasite's life cycle at both the exoerythrocytic (liver) and erythrocytic (red blood cell) stages, making it a potent remedy for malaria.

• Safety: Atovaquone-Proguanil's side effects appear comparable to those of other therapies. As with all medications, it is essential to be aware of any potential adverse effects before starting therapy.

• Resistance Management: In situations where Plasmodium falciparum is developing resistance to advised therapies, Atovaquone-Proguanil can be a useful substitute.

How Are Atovaquone and Proguanil Hydrochloride Combinations Administered?

• Proguanil and Atovaquone are combined into a tablet that is taken orally.

• If people take Atovaquone and Proguanil to prevent malaria, they will likely begin taking them once daily, one or two days before visiting a region where malaria is prevalent.

• People will then continue to take them once daily during the trip and for seven days following their return.

• If they are treating malaria with them, people will most likely take Atovaquone and Proguanil once a day for three days in a row.

• Proguanil and Atovaquone should always be taken with food or a milky beverage.

• Take Proguanil and Atovaquone daily at around the same time.

• Please carefully read the instructions on the label of any prescription you are taking and contact the pharmacist or doctor if you have any questions. Adhere to the directions on Atovaquone and Proguanil exactly.

• If people are having problems swallowing, smash the tablets and combine them with condensed milk just before taking them.

• Take another full dosage of Atovaquone and Proguanil if people throw up within 60 minutes of taking them.

What Are the Side Effects of the Atovaquone and Proguanil Hydrochloride Combination?

Proguanil and Atovaquone may have adverse effects. If any of these symptoms are severe or persistent, let the doctor know:

• Nausea.

• Vomiting.

• Stomach pain.

• Diarrhea.

• Loss of appetite.

• Headache.

• Lightheadedness.

• Cough.

• Mouth sores.

Certain adverse effects of Proguanil with Atovaquone may be dangerous.

Give the doctor a call right away if people encounter any of the following symptoms:

• Rash.

• Hives.

• Blistering or peeling skin.

• Fever.

• There is swelling in the hands, feet, ankles, lower legs, lips, tongue, eyes, and throat.

• Breathing or swallowing difficulties.

• Hoarseness or tightness in the throat.

• Yellow eyes or skin, black urine, lethargy, appetite loss, or pain in the upper right stomach area.

Proguanil with Atovaquone may have additional negative effects. If people have any odd side effects while taking Proguanil with Atovaquone, contact the doctor.

What Are the Things to Inform the Doctor Before Taking Atovaquone and Proguanil Hydrochloride Combination?

1. People with an allergy to Proguanil or Atovaquone should avoid using the combination. People with severe kidney disease should not use this medication to prevent malaria.

2. To be sure people can safely take Proguanil and Atovaquone combination, tell the doctor if people have any of these other conditions:

• Kidney disease.

• Liver disease.

• Serious complications from malaria.

• Uncontrolled diarrhea or vomiting.

3. The Proguanil and Atovaquone combination is safe for fetuses, but pregnant women should discuss malaria risks with their doctor, especially in prevalent areas. The combination can enter breast milk and harm nursing babies. It is not recommended to treat or prevent malaria in children under 11 pounds or stop the illness in those under 24 pounds.

Dietary Considerations:

Any dietary, beverage, or exercise limitations should be adhered to as directed by the doctor.

Missed Dose:

The missed dose of the Proguanil and Atovaquone combination should be taken as soon as people remember. If the next dose approaches, skip the missed Proguanil and Atovaquone combination. Never take more of the Proguanil and Atovaquone combination to make up for a missed dosage.

Overdose:

Symptoms of the Proguanil and Atovaquone combination overdose can include,

• Nausea.

• Vomiting.

• Mouth sores.

• Hair loss.

• Bruising or bleeding easily.

• Skin peeling on the hands or feet.

Storage and Handling

Proguanil and Atovaquone combination tablets should be stored at 25°C (degrees Celsius) or 77°F (degrees Fahrenheit), with temperature variations permitted between 15 and 30°C (59 and 86°F). They must also be kept out of children's reach, securely locked, and in their original containers.

Disposal

It is essential to appropriately dispose of unnecessary Proguanil and Atovaquone combination tablets to prevent pets, kids, and others from consuming them. To ensure appropriate disposal, use the FDA's medicine take-back program rather than flushing them down the toilet.

For Doctors

What Are the Pharmacological Actions of Proguanil and Atovaquone?

Pharmacodynamics

The way Proguanil and Atovaquone combination affects the human QT interval is uncertain.

Mechanism of Action

A combination of Proguanil hydrochloride and Atovaquone interferes with two pathways necessary to produce pyrimidines needed for nucleic acid replication. While Proguanil hydrochloride largely acts through cycloguanil, a dihydrofolate reductase inhibitor, to disrupt the formation of deoxy thymidylate, Atovaquone specifically inhibits the electron transport of parasite mitochondria.

Pharmacokinetics

• Absorption: The lipophilic compound Atovaquone has a variable bioavailability. The optimal way to take it is with food or a milky drink; dietary fat improves absorption. When taken with food, the bioavailability of the tablet formulation is 23 percent. Oral dosages of 50 to 500 mg of Proguanil are readily absorbed.

• Distribution: Atovaquone is a highly protein-bound medication with an apparent volume distribution of 8.8 L/kg (liters per kilogram) after oral administration. It is distributed in adult and pediatric patients at concentrations of 1 to 90 mcg/mL (micrograms per milliliter). Proguanil has an apparent volume fraction of 1,617 to 2,502 L (liters) in adult and pediatric patients over 15 and 462 to 966 L in pediatric patients who weigh between 24 and 123 pounds. The combination of Atovaquone and Proguanil does not alter their binding in human plasma.

• Metabolism: Atovaquone, a drug with a restricted metabolism, can be ineffective in populations at risk of malaria infection, such as those in Asia and Africa, due to insufficient therapeutic levels of Cycloguanil, even after multiple doses.

• Excretion: Atovaquone and Proguanil have long elimination half-lives due to enterohepatic cycling and fecal elimination. Proguanil has a 12 to 21-hour half-life in adult and pediatric patients, while Atovaquone has a two- to three-day half-life in adult patients. Their apparent clearance (CL/F) is correlated with body weight, with higher CL/F values for those over 24 pounds.

What Are the Drug Interactions?

• Rifampin or Rifabutin: Atovaquone concentrations can be lowered by Rifampin or Rifabutin, although concurrent use of Atovaquone and Proguanil with Rifampin or Rifabutin is not advised.

• Anticoagulants: Although the exact mechanism is uncertain, Proguanil may increase the anticoagulant action of Warfarin and other Coumarin-based anticoagulants. When starting or stopping Atovaquone and Proguanil in individuals using anticoagulants, caution is advised; coagulation tests should be regularly watched.

• Tetracycline: Tetracycline may lower Atovaquone levels; parasitemia must be continuously monitored.

• Metoclopramide: Although Metoclopramide may be administered to patients receiving Atovaquone and Proguanil, it should only be used if other antiemetics are unavailable because it may reduce Atovaquone's bioavailability.

• Indinavir: When Atovaquone and Indinavir were administered together, the steady-state AUC (area under the curve) and Cmax (maximum concentration) of Indinavir remained unchanged; however, the Ctrough concentration decreased, suggesting that Atovaquone and Indinavir should be prescribed with caution.

Clinical Studies

• Prevention of P. Falciparum Malaria: Participants were drawn from three 10- to 12-week placebo-controlled trials conducted in malaria-endemic regions of Kenya, Zambia, and Gabon. For reasons unrelated to parasitemia, 19 of the 165 children who received the Atovaquone and Proguanil combination and 18 of the patients who received a placebo withdrew from the research. Among the 144 evaluable placebo recipients, 31 (22 percent) experienced P. falciparum parasitemia, but only one out of 150 evaluable patients (less than one percent) experienced this when on Atovaquone and Proguanil. The exposure rate to P. falciparum malaria in both active-controlled trials, which involved non-immune tourists visiting a malaria-endemic area, was unclear. Both Atovaquone and Proguanil hydrochloride were independently demonstrated to have causative prophylactic action against P. falciparum liver-stage parasites in small-volunteer trials.

• Treatment of Acute, Uncomplicated P. Falciparum Malaria Infections: For the treatment of acute, uncomplicated malaria brought on by P. falciparum, three Phase 2 clinical trials assessed Atovaquone alone, Proguanil hydrochloride alone, and a combination of Atovaquone and Proguanil hydrochloride. With Atovaquone alone, the parasitological cure rate was 66 percent; with Proguanil hydrochloride alone, it was six percent; and with the combination, it was 100 percent. Eight Phase 3 randomized, open-label, controlled clinical trials involving 16 percent of children aged 12 years or less and a mean age of 27 years were conducted to assess Atovaquone and Proguanil. When combined with two more trials assessing Atovaquone and Proguanil alone, the overall effectiveness of Atovaquone and Proguanil in treating the erythrocytic phase of non-falciparum malaria was 98.7 percent. When P. vivax malaria was treated with Atovaquone and Proguanil alone, parasite relapse frequently occurred; relapsing malaria requires extra treatment to avoid relapse.

Use in Specific Populations

• Pregnancy: Although Atovaquone and Proguanil, a pregnancy category C (animal studies indicate fetal harm, while human studies are scarce, but potential benefits may justify drug use in pregnant women despite risks) medication, have been associated with higher resorption and fetal damage, their usage ought to be restricted to cases in which other options are unavailable.

• Breastfeeding: There is not much data on Atovaquone and Proguanil excretion into human milk, and as animal studies have different results, caution should be advised while giving these medications to nursing mothers.

• Pediatric Use: Controlled trials with patients weighing 24 pounds or less have not proved the safety and efficacy of Atovaquone and Proguanil in pediatric malaria prophylaxis. Treatment for malaria in pediatric kids weighing less than 11 pounds has not been proven to be safe or effective.

• Geriatric Use: Subjects 65 and older were not sufficiently studied in the Atovaquone and Proguanil clinical trials, suggesting that elderly patients should use caution when selecting a dose due to increased risks associated with cycloguanil exposure, increased hepatic, renal, and cardiac function problems, and a higher frequency of concomitant disease or other drug therapy.

• Renal impairment: Atovaquone and Proguanil are not advised in individuals with significant renal impairment to prevent P. falciparum malaria.

• Hepatic impairment: There is no need to change the dosage for individuals with mild or moderate hepatic impairment, and no trials have been done for patients with severe hepatic impairment.