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Atovaquone

Pronunciation

(a TOE va kwone)

Dosage Forms

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

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Suspension, Oral:

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

Generic: 750 mg/5 mL (210 mL)

Brand Names: U.S.

  • Mepron

Pharmacologic Category

  • Antiprotozoal

Pharmacology

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

Absorption

Oral:

Infants and Children <2 years of age: Decreased absorption

Adults: Oral suspension: Absorption is enhanced 1.4-fold with food; decreased absorption with single doses exceeding 750 mg

Distribution

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

Metabolism

Undergoes enterohepatic recirculation

Excretion

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

Time to Peak

Dual peak serum concentrations at 1 to 8 hours and at 24 to 96 hours after dose due to enterohepatic cycling

Half-Life Elimination

Children (4 months to 12 years): 60 hours (range: 31-163 hours); Adults: 2.9 days; Adults with AIDS: 2.2 days

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: Unlabeled

Treatment of babesiosis; treatment/chronic maintenance of Toxoplasma gondii encephalitis; primary prophylaxis of HIV-infected persons at high risk for developing Toxoplasma gondii encephalitis

Contraindications

Hypersensitivity to atovaquone or any component of the formulation

Dosage

Pneumocystis jirovecii pneumonia (PCP), prevention:

Infants and Children <13 years (off-label use) (CDC 2009): Oral:

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

4 to 24 months: 45 mg/kg once daily with food

>24 months: 30 mg/kg once daily with food

Adolescents ≥13 years and Adults: Oral: 1,500 mg once daily with food

PCP, mild-to-moderate, treatment:

Infants and Children <13 years (off-label use) (CDC 2009): Oral:

Birth to 3 months: 30 to 40 mg/kg/day in 2 divided doses with food (maximum: 1,500 mg daily)

3 to 24 months: 45 mg/kg/day in 2 divided doses with food (maximum: 1,500 mg daily)

≥24 months: 30 to 40 mg/kg/day in 2 divided doses with food (maximum: 1,500 mg daily)

Adolescents ≥13 years and Adults: Oral: 750 mg twice daily with food for 21 days

Babesiosis (off-label use): Oral:

Children: 40 mg/kg/day in 2 divided doses with azithromycin for 7 to 10 days (maximum: 1,500 mg daily). Note: Relapsing infection may require at least 6 weeks of therapy (Vannier 2012).

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

Toxoplasma gondii prophylaxis in HIV-exposed/infected patients (CDC 2009): Infants and Children <13 years (off-label use; either as monotherapy or with pyrimethamine plus leucovorin): Oral:

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

4 to 24 months: 45 mg/kg once daily with food

>24 months: 30 mg/kg once daily with food

T. gondii encephalitis in HIV-infected patients (off-label use) (HHS [OI adult 2015]): Adolescents and Adults: Oral:

Prophylaxis: 1,500 mg once daily with food (either as monotherapy or with pyrimethamine plus leucovorin)

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)

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

Dosage adjustment in renal impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). However, atovaquone is not appreciably renally excreted.

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Atovaquone undergoes enterohepatic cycling and primarily hepatic excretion. Use caution in patients with severe impairment; monitor closely.

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: Separate administration of atovaquone and etoposide by at least 1-2 days. Avoid concomitant administration of atovaquone and etoposide. Consider therapy modification

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. Avoid combination

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

Adverse Reactions

Note: 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%)

Postmarketing and/or case reports (Limited to important or life-threatening): 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 Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Diagnosis and treatment of Pneumocystis jirovecii pneumonia (PCP) in pregnant women is the same as in nonpregnant women; however, information specific to the use of atovaquone in pregnancy is limited (HHS [OI adult 2015]).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, nausea, dyspepsia, diarrhea, myalgia, insomnia, dizziness, hyperhidrosis, lack of appetite, rhinitis, or rhinorrhea. Have patient report immediately to prescriber depression, dyspnea, stomatitis, severe asthenia, flu-like symptoms, or signs of hepatic impairment (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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