Atovaquone

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Oral:

Mepron: 750 mg/5 mL (5 mL, 210 mL) [contains benzyl alcohol; citrus flavor]

Generic: 750 mg/5 mL (5 mL, 210 mL)

Pharmacology

Mechanism of Action

Inhibits electron transport in mitochondria resulting in the inhibition of key metabolic enzymes responsible for the synthesis of nucleic acids and ATP

Pharmacokinetics/Pharmacodynamics

Absorption

Enhanced ~2-fold with food

Distribution

V_dss: 0.6 ± 0.17 L/kg; CSF concentration is <1% of the plasma concentration

Metabolism

Unknown

Excretion

Feces (>94% as unchanged drug); urine (<1%)

Half-Life Elimination

Range: 67 ± 33.4 hours to 77.6 ± 23.1 hours

Protein Binding

>99%

Use: Labeled Indications

Pneumocystis jirovecii pneumonia (PCP), prophylaxis: Prevention of PCP in adults and adolescents 13 years and older who are intolerant to trimethoprim-sulfamethoxazole (TMP-SMZ)

Pneumocystis jirovecii pneumonia (PCP), treatment: Acute oral treatment of mild to moderate PCP in adults and adolescents 13 years and older who are intolerant to TMP-SMZ

Use: Off Label

Babesiosisbyes

Data from a prospective, nonblinded, randomized trial in patients with non-life-threatening babesiosis, supports the use of atovaquone (in combination with azithromycin) for the treatment of this condition Krause 2000. Clinical experience also suggests the utility of atovaquone (in combination with azithromycin) for the treatment of immunocompetent patients with mild to moderate babesiosis Vannier 2012. Additional trials may be necessary to further define the role of atovaquone in the treatment of this condition.

Based on the Infectious Diseases Society of America (IDSA) guidelines for the clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis, atovaquone (in combination with azithromycin) is effective and recommended for the treatment of mild to moderate babesiosis.

Toxoplasma gondii encephalitis (prophylaxis/treatment/chronic maintenance) in HIV-infected patientsyes

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, atovaquone is an effective and recommended agent for prophylaxis, treatment, or as chronic maintenance therapy for T. gondii encephalitis in HIV-infected patients.

Contraindications

Hypersensitivity to atovaquone or any component of the formulation

Dosage and Administration

Dosing: Adult

Pneumocystis jirovecii pneumonia (PCP), prevention: Oral: 1,500 mg once daily with food

PCP, mild to moderate, treatment: Oral: 750 mg twice daily with food for 21 days

Babesiosis (off-label use): Oral: 750 mg twice daily with azithromycin for at least 7 to 10 days; Note: Relapsing infection may require at least 6 weeks of therapy (Krauss 2000; Vannier 2012).

Toxoplasma gondii encephalitis in HIV-infected patients (off-label use; alternative agent) (HHS [OI adult 2017]): Oral:

Prophylaxis: 1,500 mg once daily with food (either as monotherapy or with pyrimethamine plus leucovorin); primary prophylaxis is indicated for Toxoplasma IgG-positive patients with CD4 count <100 cells/mm³. Continue primary prophylaxis following initiation of ART until CD4 count >200 cells/mm³ for >3 months; some experts discontinue primary prophylaxis in patients with a CD4 count between 100 to 200 cells/mm³ who are receiving ART and have had an undetectable viral load for ≥3 to 6 months

Treatment: 1,500 mg twice daily with food (either with pyrimethamine plus leucovorin, or with sulfadiazine, or as monotherapy) for at least 6 weeks (longer if extensive disease or incomplete response)

Secondary prophylaxis (chronic maintenance): 750 to 1,500 mg twice daily with food (either with pyrimethamine plus leucovorin, or with sulfadiazine, or as monotherapy); may discontinue when asymptomatic and CD4 count >200 cells/mm³ for >6 months in response to antiretrovirals

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Pneumocystis jirovecii pneumonia (PCP) (HIV-exposed/-positive) (HHS [adult OI 2017, pediatric OI 2016]): Limited data available in ages <13 years:

Prophylaxis; primary or secondary:

Infants and Children: Oral:

1 to 3 months: 30 mg/kg/day once daily

4 to 24 months: 45 mg/kg/day once daily

>24 months: 30 mg/kg/day once daily; maximum daily dose: 1,500 mg/day

Adolescents: Oral: 1,500 mg once daily

Treatment; mild to moderate infection: Treatment duration: 21 days

Infants and Children: Oral:

1 to 3 months: 30 to 40 mg/kg/day divided once or twice daily

4 to 24 months: 45 mg/kg/day divided once or twice daily

>24 months: 30 to 40 mg/kg/day divided once or twice daily; maximum daily dose: 1,500 mg/day

Adolescent: Oral: 750 mg twice daily

Toxoplasmosis (toxoplasma gondii); encephalitis (HIV-exposed/-positive) (HHS [adult OI 2017, pediatric OI 2016]): Limited data available:

Primary prophylaxis:

Infants and Children: Oral:

1 to 3 months: 30 mg/kg/day once daily

4 to 24 months: 45 mg/kg/day once daily; with or without pyrimethamine/leucovorin

>24 months: 30 mg/kg/day once daily; maximum daily dose: 1,500 mg/day

Adolescents: Oral: 1,500 mg once daily; with or without pyrimethamine/leucovorin

Treatment (encephalitis): Adolescents: Oral: 1,500 mg twice daily for at least 6 weeks (longer if extensive disease or incomplete response); use in combination with pyrimethamine/leucovorin or sulfadiazine is preferred

Secondary prophylaxis/chronic maintenance therapy (suppressive):

Infants and Children: Oral:

1 to 3 months: 30 mg/kg/day once daily with leucovorin

4 to 24 months: 45 mg/kg/day once daily; with or without pyrimethamine/leucovorin

>24 months: 30 mg/kg/day once daily; maximum daily dose: 1,500 mg/day; with leucovorin

Adolescents: Oral: 750 to 1,500 mg twice daily; use in combination with pyrimethamine/leucovorin or sulfadiazine is preferred

Babesiosis: Limited data available (IDSA [Wormser 2006]):

Infants and Children: Oral: 40 mg/kg/day divided twice daily; maximum daily dose: 1,500 mg/day with azithromycin for 7 to 10 days

Adolescents: Oral: 750 mg twice daily for 7 to 10 days with azithromycin

Administration

Oral: Must administer with food. Shake suspension gently before use. Once opened, a foil pouch can be emptied on a dosing spoon, in a cup, or directly into the mouth.

Dietary Considerations

Must be taken with food.

Storage

Store at 15°C to 25°C (59°F to 77°F). Do not freeze.

Drug Interactions

Efavirenz: May decrease the serum concentration of Atovaquone. Management: Consider alternatives to the use of atovaquone with efavirenz when possible. If this combination must be used, monitor for evidence of reduced atovaquone clinical effectiveness. Consider therapy modification

Etoposide: Atovaquone may increase the serum concentration of Etoposide. Management: Consider separating the administration of atovaquone and etoposide by at least 1 to 2 days. Monitor therapy

Etoposide Phosphate: Atovaquone may increase the serum concentration of Etoposide Phosphate. Management: Consider separating the administration of atovaquone and etoposide by at least 1 to 2 days. Monitor therapy

Indinavir: Atovaquone may decrease the serum concentration of Indinavir. Monitor therapy

Metoclopramide: May decrease the serum concentration of Atovaquone. Management: Consider alternatives to metoclopramide when possible; atovaquone should only be used with metoclopramide if no other antiemetics are available. Consider therapy modification

Rifamycin Derivatives: May decrease the serum concentration of Atovaquone. Avoid combination

Ritonavir: May decrease the serum concentration of Atovaquone. Monitor therapy

Tetracycline (Systemic): May decrease the serum concentration of Atovaquone. Monitor therapy

Adverse Reactions

Frequency not always defined. Adverse reaction statistics have been compiled from studies including patients with advanced HIV disease. Consequently, it is difficult to distinguish reactions attributed to atovaquone from those caused by the underlying disease or a combination thereof.

>10%:

Central nervous system: Headache (16% to 31%), insomnia (10% to 19%), depression, pain

Dermatologic: Skin rash (22% to 46%), pruritus (5% to ≥10%), diaphoresis

Gastrointestinal: Diarrhea (19% to 42%), nausea (21% to 32%), vomiting (14% to 22%), abdominal pain (4% to 21%)

Infection: Infection (18% to 22%)

Neuromuscular & skeletal: Weakness (8% to 31%), myalgia

Respiratory: Cough (14% to 25%), rhinitis (5% to 24%), dyspnea (15% to 21%), sinusitis (7% to ≥10%), flu-like symptoms

Miscellaneous: Fever (14% to 40%)

1% to 10%:

Cardiovascular: Hypotension (≤1%)

Central nervous system: Dizziness (3% to 8%), anxiety (≤7%)

Endocrine & metabolic: Hyponatremia (7% to 10%), hyperglycemia (≤9%), increased amylase (7% to 8%), hypoglycemia (≤1%)

Gastrointestinal: Oral candidiasis (5% to 10%), anorexia (≤7%), dyspepsia (≤5%), constipation (≤3%), dysgeusia (≤3%)

Hematologic & oncologic: Anemia (4% to 6%), neutropenia (3% to 5%)

Hepatic: Increased liver enzymes (4% to 8%)

Renal: Increased blood urea nitrogen (≤1%), increased serum creatinine (≤1%)

Respiratory: Bronchospasm (2% to 4%)

<1%, postmarketing, and/or case reports: Acute renal failure, angioedema, constriction of the pharynx, corneal disease (vortex keratopathy), desquamation, erythema multiforme, hepatic failure (rare), hepatitis (rare), hypersensitivity reaction, methemoglobinemia, pancreatitis, Stevens-Johnson syndrome, thrombocytopenia, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Diarrhea/vomiting: Absorption may be decreased in patients who have diarrhea or vomiting; monitor closely and consider use of an antiemetic. If severe, consider use of an alternative antiprotozoal.
• Hypersensitivity: Hypersensitivity reactions (eg, angioedema, bronchospasm, throat tightness, urticaria) have occurred.

Disease-related concerns:

• Gastrointestinal disorders: Consider parenteral therapy with alternative agents in patients who have difficulty taking atovaquone with food. Gastrointestinal disorders may limit absorption of oral medications; may not achieve adequate plasma levels.
• Hepatic impairment: Use with caution in patients with severe hepatic impairment; monitor closely; rare cases of cholestatic hepatitis, elevated liver function tests, and fatal liver failure have been reported.
• Pneumocystis jirovecii pneumonia (PCP): Appropriate use: When used for treatment, has only been indicated in mild to moderate PCP; not studied for use in severe PCP; atovaquone has less adverse effects than trimethoprim-sulfamethoxazole (TMP-SMZ) (the treatment of choice for mild to moderate PCP), although atovaquone is less effective than TMP-SMZ (HHS [OI adult 2015]).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution in elderly patients.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

Monitoring Parameters

Hepatic function at baseline (monitor closely during treatment in patients with severe hepatic impairment), hypersensitivity reactions, CD4 count (for chronic maintenance treatment in toxoplasmosis), patient’s food tolerance/ability to take atovaquone, post-dose vomiting, diarrhea

Pregnancy

Pregnancy Considerations

Information specific to the use of atovaquone in pregnancy is limited.

Diagnosis and treatment of Pneumocystis jirovecii pneumonia (PCP) in pregnant women is the same as in nonpregnant women. Atovaquone may be used as an alternative agent for PCP and Toxoplasma gondii infections when needed in pregnancy (HHS [OI adult 2017]).

Patient Education

What is this drug used for?

• It is used to prevent Pneumocystis jirovecii pneumonia.
• It is used to treat Pneumocystis jirovecii pneumonia.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Headache
• Nausea
• Vomiting
• Diarrhea
• Muscle pain
• Trouble sleeping
• Flu-like symptoms
• Sweating a lot
• Stuffy nose
• Runny nose

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Depression
• Thrush
• Cough
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.