What are the indications for Atovaquone (antiprotozoal medication)?

Indications for Atovaquone

Atovaquone is FDA-approved for two specific indications: prevention of Pneumocystis jirovecii pneumonia (PCP) in patients aged 13 years and older who cannot tolerate trimethoprim-sulfamethoxazole (TMP-SMX), and treatment of mild-to-moderate PCP in the same population who are TMP-SMX intolerant. 1

FDA-Approved Indications

Prevention of PCP

• Atovaquone 1,500 mg (10 mL) once daily with food is indicated for PCP prophylaxis in adults and adolescents aged ≥13 years who cannot tolerate TMP-SMX 1
• This represents a second-line prophylactic option when the preferred agent (TMP-SMX) cannot be used 2

Treatment of Mild-to-Moderate PCP

• Atovaquone 750 mg (5 mL) twice daily with food for 21 days is indicated for acute treatment of mild-to-moderate PCP (alveolar-arterial oxygen gradient ≤45 mm Hg) in adults and adolescents aged ≥13 years who cannot tolerate TMP-SMX 1
• The FDA label explicitly states that treatment of severe PCP (A-a gradient >45 mm Hg) has not been studied and is not an approved indication 1
• Efficacy in patients failing TMP-SMX therapy has also not been established 1

Guideline-Supported Uses

PCP Treatment in HIV-Infected Patients

• CDC/NIH/IDSA guidelines recommend atovaquone as an alternative therapeutic regimen for mild-to-moderate PCP when patients are TMP-SMX intolerant or when clinical treatment fails after 5-7 days of TMP-SMX 2
• For adults, this carries a BI recommendation strength 2
• For children, dosing is 30-40 mg/kg/day in 2 divided doses with fatty foods; infants aged 3-24 months may require 45 mg/kg/day 2
• Atovaquone may be considered to complete a 21-day course after 7-10 days of IV pentamidine in patients showing clinical improvement 2

PCP Prophylaxis in HIV-Infected Patients

• Atovaquone is recommended as an alternative prophylactic agent for PCP when TMP-SMX cannot be tolerated 2
• The 1999 USPHS/IDSA guidelines note that atovaquone appears as effective as aerosolized pentamidine or dapsone for prophylaxis, though substantially more expensive 2
• For HIV-infected children >12 months requiring PCP prophylaxis, atovaquone might also provide protection against toxoplasmosis 2

Toxoplasmosis Prophylaxis (Potential Benefit)

• When administered for PCP prophylaxis in children, atovaquone might also provide protection against toxoplasmosis, though this is a CIII recommendation 2
• This dual protection is relevant for severely immunosuppressed children who are Toxoplasma-seropositive 2

Use in Transplant Recipients

• Atovaquone 750 mg once daily has been studied for PCP prophylaxis in liver transplant recipients intolerant to TMP-SMX 3
• In a preliminary study of 28 liver transplant patients, no cases of PCP developed over 1 year, though this requires further validation 3

Critical Administration Requirements

Food Requirement

• Atovaquone MUST be administered with food, particularly fatty foods, as bioavailability increases 1.4-fold compared to fasting state 2, 1
• Failure to administer with food may result in suboptimal plasma concentrations and treatment failure 1

Gastrointestinal Absorption Concerns

• Patients with gastrointestinal disorders may have limited absorption resulting in suboptimal atovaquone concentrations 1
• This is a critical consideration when selecting atovaquone, as malabsorption can lead to therapeutic failure

Important Limitations and Contraindications

Not Indicated For:

• Severe PCP (A-a gradient >45 mm Hg) - this has not been studied and is not an approved indication 1
• Patients failing TMP-SMX therapy - efficacy not established 1
• First-line treatment when TMP-SMX can be tolerated 2

Contraindications:

• Known serious allergic/hypersensitivity reactions (angioedema, bronchospasm, throat tightness, urticaria) to atovaquone or any component 1

Comparative Efficacy Considerations

• Atovaquone is slightly less effective than TMP-SMX for PCP treatment but has a significantly better safety profile 4, 5
• Atovaquone has equivalent efficacy to IV pentamidine for mild-to-moderate PCP but with fewer treatment-limiting adverse effects 4, 5
• For prophylaxis, atovaquone 1,500 mg once daily has similar efficacy to aerosolized pentamidine 6
• The 750 mg daily dose showed higher incidence of PCP and death compared to 1,500 mg daily in prophylaxis studies 6

Adverse Effects Profile

• Most common adverse reactions include rash (10-15%), nausea, diarrhea, and elevated liver enzymes 2, 1
• Atovaquone does not cause bone marrow suppression, a significant advantage over TMP-SMX 4
• Most adverse reactions occur after the first week of therapy 2
• Hepatotoxicity with elevated liver chemistry tests and cases of hepatitis and fatal liver failure have been reported 1

Drug Interactions

• Atovaquone concentrations are increased by fluconazole and prednisone 2
• Atovaquone concentrations are decreased by rifampin, rifabutin, acyclovir, opiates, cephalosporins, tetracycline, metoclopramide, and benzodiazepines 2, 1
• Concomitant use with rifampin or rifabutin is not recommended 1
• Atovaquone reduces indinavir trough concentrations; monitor for potential loss of indinavir efficacy if coadministration is necessary 1