Clinical medicine profile
Atovaquone
Antimalarial [EPC], Antiprotozoal [EPC]
- Route
- ORAL / PARENTERAL (severe malaria)
- Schedule
- POM
- ATC
- Not assigned
- PPB status
- registered
Safety essentials
The information most likely to change a prescribing or dispensing decision.
Contraindications
- 4 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.
- Known serious allergic/hypersensitivity reaction (e.g., angioedema, bronchospasm, throat tightness, urticaria) to atovaquone or any of the components of atovaquone oral suspension.
Precautions
- 5 WARNINGS AND PRECAUTIONS Failure to administer atovaquone oral suspension with food may result in lower plasma atovaquone concentrations and may limit response to therapy.
- Patients with gastrointestinal disorders may have limited absorption resulting in suboptimal atovaquone concentrations.
- ( 5.1 ) Hepatotoxicity: Elevated liver chemistry tests and cases of hepatitis and fatal liver failure have been reported.
- ( 5.2 ) 5.1 Risk of Limited Oral Absorption Absorption of orally administered atovaquone oral suspension is limited but can be significantly increased when the drug is taken with food.
- Failure to administer atovaquone oral suspension with food may result in lower plasma atovaquone concentrations and may limit response to therapy.
- Consider therapy with other agents in patients who have difficulty taking atovaquone oral suspension with food or in patients who have gastrointestinal disorders that may limit absorption of oral medications [see Clinical Pharmacology ( 12.3 )]. 5.2 Hepatotoxicity Cases of cholestatic hepatitis, elevated liver enzymes, and fatal liver failure have been reported in patients treated with atovaquone [see Adverse Reactions ( 6.2 )].
- If treating patients with severe hepatic impairment, closely monitor patients following administration of atovaquone oral suspension.
Dosing matrix
Population and organ-function guidance, shown together for faster comparison.
2 DOSAGE AND ADMINISTRATION Prevention of PCP: 1,500 mg (10 mL) once daily with food ( 2.1 ) Treatment of PCP: 750 mg (5 mL) twice daily with food for 21 days ( 2.2 ) Supplied in Bottles: Shake bottle gently before use. ( 2.3 ) 2.1 Dosage for the Prevention of P. jirovecii Pneumonia The recommended oral dosage is 1,500 mg (10 mL) once daily administered with food. 2.2 Dosage for the Treatment of Mild-to-Moderate P. jirovecii Pneumonia The recommended oral dosage is 750 mg (5 mL) twice daily (total daily dose = 1,500 mg) administered with food for 21 days. 2.3 Important Administration Instructions Administer atovaquone oral suspension with food to avoid lower plasma atovaquone concentrations that may limit response to therapy [see Warnings and Precautions ( 5.1), Clinical Pharmacology ( 12.3 )] . Atovaquone Oral Suspension Bottle Shake bottle gently before administering the recommended dosage.
8.4 Pediatric Use Evidence of safety and effectiveness in pediatric patients (aged 12 years and younger) has not been established. In a trial of atovaquone oral suspension administered once daily with food for 12 days to 27 HIV-1-infected, asymptomatic infants and children aged between 1 month and 13 years, the pharmacokinetics of atovaquone were age-dependent. The average steady-state plasma atovaquone concentrations in the 24 subjects with available concentration data are shown in Table 5. Table 5. Average Steady-state Plasma Atovaquone Concentrations in Pediatric Subjects C ss = Concentration at steady state. Age Dose of Atovaquone Oral Suspension 10 mg/kg 30 mg/kg 45 mg/kg Average C ss in mcg/mL (mean ± SD) 1-3 months 5.9 (n = 1) 27.8 ± 5.8 (n = 4) _ >3-24 months 5.7 ± 5.1 (n = 4) 9.8 ± 3.2 (n = 4) 15.4 ± 6.6 (n = 4) >2-13 years 16.8 ± 6.4 (n = 4) 37.1 ± 10.9 (n = 3) _
Caution absorption.
- CrCl 0–120: See renal_dose_adjustment; confirm product SmPC.
Caution.
Use, effects & interactions
Indications
- 1 INDICATIONS AND USAGE Atovaquone oral suspension is a quinone antimicrobial drug indicated for: Prevention of Pneumocystis jirovecii pneumonia (PCP) in adults and adolescents aged 13 years and older who cannot tolerate trimethoprim-sulfamethoxazole (TMP-SMX).
- ( 1.1 ) Treatment of mild-to-moderate PCP in adults and adolescents aged 13 years and older who cannot tolerate TMP-SMX.
- ( 1.2 ) Limitations of Use ( 1.3 ): Treatment of severe PCP (alveolar arterial oxygen diffusion gradient [(A-a)DO 2 ] >45 mm Hg) with atovaquone oral suspension has not been studied.
- The efficacy of atovaquone oral suspension in subjects who are failing therapy with TMP-SMX has also not been studied. 1.1 Prevention of Pneumocystis jirovecii Pneumonia Atovaquone oral suspension is indicated for the prevention of Pneumocystis jirovecii pneumonia (PCP) in adults and adolescents (aged 13 years and older) who cannot tolerate trimethoprim-sulfamethoxazole (TMP-SMX). 1.2 Treatment of Mild-to-Moderate Pneumocystis jirovecii Pneumonia Atovaquone oral suspension is indicated for the acute oral treatment of mild-to-moderate PCP in adults and adolescents (aged 13 years and older) who cannot tolerate TMP-SMX. 1.3 Limitations of Use Clinical experience with atovaquone for the treatment of PCP has been limited to subjects with mild-to-moderate PCP (alveolar-arterial oxygen diffusion gradient [(A-a)DO 2 ] ≤45 mm Hg).
- Treatment of more severe episodes of PCP with atovaquone has not been studied.
- The efficacy of atovaquone in subjects who are failing therapy with TMP-SMX has also not been studied.
Adverse effects
- 6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Hepatotoxicity [see Warnings and Precautions ( 5.2 )] .
- PCP Prevention: The most frequent adverse reactions (≥25% that required discontinuation) were diarrhea, rash, headache, nausea, and fever.
- ( 6.1 ) PCP Treatment: The most frequent adverse reactions (≥14% that required discontinuation) were rash (including maculopapular), nausea, diarrhea, headache, vomiting, and fever.
- ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Additionally, because many subjects who participated in clinical trials with atovaquone had complications of advanced human immunodeficiency virus (HIV) disease, it was often difficult to distinguish adverse reactions caused by atovaquone from those caused by underlying medical conditions.
- PCP Prevention Trials In 2 clinical trials, atovaquone oral suspension was compared with dapsone or aerosolized pentamidine in HIV-1-infected adolescent (13 to 18 years) and adult subjects at risk of PCP (CD4 count <200 cells/mm 3 or a prior episode of PCP) and unable to tolerate TMP-SMX.
- Dapsone Comparative Trial: In the dapsone comparative trial (n = 1,057), the majority of subjects were white (64%), male (88%), and receiving prophylaxis for PCP at randomization (73%)
- the mean age was 38 years.
- Subjects received atovaquone oral suspension 1,500 mg once daily (n = 536) or dapsone 100 mg once daily (n = 521)
- median durations of exposure were 6.7 and 6.5 months, respectively.
- Adverse reaction data were collected only for adverse reactions requiring discontinuation of treatment, which occurred at similar frequencies in subjects treated with atovaquone oral suspension or dapsone (Table 1).
- Among subjects taking neither dapsone nor atovaquone at enrollment (n = 487), adverse reactions requiring discontinuation of treatment occurred in 43% of subjects treated with dapsone and 20% of subjects treated with atovaquone oral suspension.
- Gastrointestinal adverse reactions (nausea, diarrhea, and vomiting) were more frequently reported in subjects treated with atovaquone oral suspension (Table 1).
- Table 1.
Drug interactions
Open multi-drug checker ↗- Kenya: follow current MoH malaria guidelines for uncomplicated vs severe disease.
- Test before treat when feasible.
- Complete full ACT course.
- Severe malaria is an emergency — parenteral artesunate, not oral therapy alone.
Mechanism & disposition
12.
Read complete mechanism
12.1 Mechanism of Action Atovaquone is a quinone antimicrobial drug [see Clinical Pharmacology ( 12.4 )] . Artemisinins generate carbon-centred free radicals after activation by parasite haem-iron, damaging parasite proteins and membranes — rapid blood schizonticidal effect. Partner drugs (lumefantrine, piperaquine, etc.) provide longer-acting clearance of residual parasites. Other classes act on haem detoxification, electron transport, or folate pathways depending on agent.
Hours (artemisinins rapid parasite clearance)
Regimen-dependent (ACT 3 days typical)
ORAL / PARENTERAL (severe malaria)
Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone is highly dependent on formulation and diet. The absolute bioavailability of a 750-mg dose of atovaquone oral suspension administered under fed conditions in 9 HIV-1-infected...
Following IV administration of atovaquone, the volume of distribution at steady state (Vd ss ) was 0.60 ± 0.17 L/kg (n = 9). Atovaquone is extensively bound to plasma proteins (99.9%) over the concentration range of 1 to 90 mcg/mL. In 3 HIV-1-infected children who received 750 mg...
The plasma clearance of atovaquone following IV administration in 9 HIV-1-infected volunteers was 10.4 ± 5.5 mL/min (0.15 ± 0.09 mL/min/kg). The
of atovaquone was 62.5 ± 35.3 hours after IV administration and ranged from 67 ± 33.4 to 77.6 ± 23.1 hours across trials following administration of atovaquone oral suspension. The half-life of atovaquone is due to presumed enterohepatic cycling and eventual fecal
Pregnancy, lactation & diet
8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Atovaquone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Atovaquone was not teratogenic and did not cause reproductive toxicity in rats at plasma concentrations up to 2 to 3 times the estimated human exposure (dose of 1,000 mg/kg/day in rats). Atovaquone caused maternal toxicity in rabbits at plasma concentrations that were approximately one-half the estimated human exposure. Mean fetal body lengths and weights were decreased and there were higher numbers of early resorption and post-implantation loss per dam (dose of 1,200 mg/kg/day in rabbits). It is not clear whether these effects were caused by atovaquone directly or were secondary to maternal toxicity. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent maternal plasma concentrations. In a separate study in rats given a single 14 C-radiolabelled dose (1,000 mg/kg), concentrations of radiocarbon in rat fetuses were 18% (middle gestation) and 60% (late gestation) of concurrent maternal plasma concentrations.
8.3 Nursing Mothers It is not known whether atovaquone is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised when atovaquone is administered to a nursing woman. In a rat study (with doses of 10 and 250 mg/kg), atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma at both doses.
Brands & loaded prices
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Sources & review state
Decision support only. Confirm patient-specific decisions against the current product SmPC, Kenya STG/EML, and professional judgement.