Atovaquone: Difference between revisions

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__NOTOC__
{{DrugProjectFormSinglePage
{{Atovaquone}}
|authorTag=
{{CMG}}


==Overview==
{{VP}}


Atovaquone is a chemical compound that belongs to the class of [[naphthalene]]s. Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of [[ubiquinone]], with antipneumocystic activity. Its average wholesale price is about $2.13 per standard 250 mg. tablet.<ref>[http://www.aegis.com/pubs/atn/1992/ATN16401.html (ATN) Atovaquone (Mepron; 566C80) Approved for Pneumocystis; Drug Development, Activism Success]</ref> It is also manufactured in the US in the liquid form, or oral suspension, under the brand name Mepron.<ref>[http://www.drugs.com/pro/mepron.html Mepron]</ref>
<!--Overview-->


Atovaquone is a medication used to treat or prevent:
|genericName=
# [[Pneumocystis pneumonia]] (PCP), although it is not approved for treatment of severe PCP.
# [[Toxoplasmosis]]. The medication has antiparasitic and therapeutic effects.
# [[Malaria]]. It is one of the two components (along with [[proguanil]]) in the drug Malarone. Malarone has fewer side effects than [[mefloquine]], but can be more expensive because it's taken daily.<ref>[http://healthlink.mcw.edu/article/979237802.html  Malarone: New Malaria Medication With Fewer Side-effects]</ref>


[[Co-trimoxazole|Trimethoprim-sulfamethoxazole]] (TMP-SMX, Bactrim) is generally considered first line therapy for PCP or toxoplasmosis. However, atovaquone may be used in patients who cannot tolerate, or are allergic to, TMP-SMX. In addition, atovaquone has the advantage of not causing [[myelosuppression]], which is an important issue in patients who have undergone [[bone marrow transplantation]].


==Category==


Antiparasitic
|aOrAn=


==US Brand Names==
a


MEPRON<sup>®</sup>
|drugClass=


==FDA Package Insert==


'''  [[Atovaquone description|Description]]'''
'''| [[Atovaquone clinical pharmacology|Clinical Pharmacology]]'''
'''| [[Atovaquone microbiology|Microbiology]]'''
'''| [[Atovaquone indications and usage|Indications and Usage]]'''
'''| [[Atovaquone contraindications|Contraindications]]'''
'''| [[Atovaquone warnings and precautions|Warnings and Precautions]]'''
'''| [[Atovaquone adverse reactions|Adverse Reactions]]'''
'''| [[Atovaquone drug interactions|Drug Interactions]]'''
'''| [[Atovaquone overdosage|Overdosage]]'''
'''| [[Atovaquone clinical studies|Clinical Studies]]'''
'''| [[Atovaquone dosage and administration|Dosage and Administration]]'''
'''| [[Atovaquone how supplied|How Supplied]]'''
'''| [[Atovaquone labels and packages|Labels and Packages]]'''


===Pill Images===
|indication=
{{TempDrugImages}}
{{PillImage|fileName=MALARONE_NDC_01730675.jpg|drugName=MALARONE|NDC=01730675|drugAuthor=GlaxoSmithKline LLC|ingredients=ATOVAQUONE[ATOVAQUONE];PROGUANIL HYDROCHLORIDE[PROGUANIL]|pillImprint=GX;CM3|dosageValue=250|dosageUnit=mg|pillColor=Pink|pillShape=Round|pillSize=11|pillScore=1}}
{{PillImage|fileName=MALARONE_NDC_01730676.jpg|drugName=MALARONE|NDC=01730676|drugAuthor=GlaxoSmithKline LLC|ingredients=ATOVAQUONE[ATOVAQUONE];PROGUANIL HYDROCHLORIDE[PROGUANIL]|pillImprint=GX;CG7|dosageValue=62.5|dosageUnit=mg|pillColor=Pink|pillShape=Round|pillSize=7|pillScore=1}}


==Mechanism of Action==


Atovaquone blocks the electron transport chain in [[mitochondria]] resulting in the inhibition of key metabolic enzymes responsible for the synthesis of nucleic acids and ATP.


==Uses==
|hasBlackBoxWarning=


====Malaria====
|adverseReactions=
Atovaquone is only available as a fixed preparation with [[proguanil]] that has been commercially available from [[GlaxoSmithKline]] since 2000 as '''Malarone'''® (sometimes abbreviated '''A+P''').  It can be used both to treat and to prevent malaria.


A "standard" tablet of Malarone contains 100&nbsp;mg of proguanil hydrochloride and 250&nbsp;mg of atovaquone. A "pediatric" tablet of Malarone contains 25&nbsp;mg of proguanil hydrochloride and 62.5&nbsp;mg of atovaquone.


====Treatment====


The adult treatment dose is four "standard" tablets once a day for three days.  In children, the drug is prescribed by body weight:
<!--Black Box Warning-->
*11 to 20&nbsp;kg: 1 "standard" tablet once daily for 3 days;
*21 to 30&nbsp;kg: 2 "standard" tablets once daily for 3 days;
*31 to 40&nbsp;kg: 3 "standard" tablets once daily for 3 days;
*41&nbsp;kg and above: use adult dose.
Malarone is not licensed for use in children weighing 10&nbsp;kg or less.  The "pediatric" tablets are ''not'' used in malaria treatment.


The advice of a specialist should always be sought when starting malaria treatment.  Malarone should not be used to treat severe malaria, when an injectable drug ([[quinine]] or [[artesunate]] in the UK; [[quinidine]] in the US) should be used instead.
|blackBoxWarningTitle=
Title


====Prevention====
|blackBoxWarningBody=
<i><span style="color:#FF0000;">ConditionName: </span></i>


Medical advice should always be taken before choosing a drug for malaria prevention. Because some strains of malaria are resistant, Malarone is not effective for malaria prevention in all parts of the world. It must be taken with a fatty meal or at least some milk to be absorbed adequately.
* Content


The adult dose is one "standard" tablet daily starting one or two days before traveling into a malaria-endemic area, and continuing throughout the stay and then for another 7 days after returning from the malarious area.
<!--Adult Indications and Dosage-->


The child dose is prescribed according to body weight:
<!--FDA-Labeled Indications and Dosage (Adult)-->
*11&ndash;20&nbsp;kg: 1 "pediatric" tablet once daily;
*21&ndash;30&nbsp;kg: 2 "pediatric" tablets once daily;
*31&ndash;40&nbsp;kg: 3 "pediatric" tablets once daily;
*41&nbsp;kg and above use adult dose.
The duration of treatment is the same as for adults.


====Resistance====
|fdaLIADAdult=


Proguanil acts as a [[mitochondrion|mitochondrial]] sensitiser and synergizes with atovaquone; also, there is a high natural frequency of [[Duodenal cytochrome B|cytochrome B]] mutants which leads to a high failure rate if atovaquone is used on its own to treat malaria.  Specific mutations (Y268S, Y268C) have been shown to confer resistance ''in vivo,''<ref>{{cite journal | author=Färnet A, Lindberg J, Gil P, ''et al.'' | title=Evidence of ''Plasmodium falciparum'' malaria resistant to atovaquone and proguoanil hydrochloride: case reports | year=2003 | journal=Brit Med J | volume=326 | pages=628&ndash;29 }}</ref><ref>{{cite journal | author=Fivelman QL, Butcher GA, Adagu IS, ''et al.'' | title=Malarone treatment failure and in-vitro confirmation of resistance of ''Plasmodium falciparum'' isolate from Lagos, Nigeria | year=2002 | journal=Malaria J | volume=1 | pages=1 }}</ref><ref>{{cite journal | author=Schwartz E, Bujanover S, Kain KC | title=Genetic confirmation of atovaquone-proguanil-resistant ''Plasmodium falciparum'' malaria acquired by a nonimmune traveller to east Africa | year=2003 | journal=Clin Infect Dis | volume=37 | pages=450&ndash;51 }}</ref> but there are other mechanisms of resistance that remain unknown.<ref>{{cite journal | author=Wichmann O, Muehlen M, Gruss H, ''et al.'' | title=Malarone treatment failure not associated with previously described mutations in the cytochrome b gene | year=2004 | journal=Malaria J | volume=3 | pages=14 }}</ref>
=====Condition1=====


==References==
* Dosing Information
{{Reflist|2}}


[[Category:Antibiotics]]
:* Dosage
[[Category:Wikinfect]]
 
=====Condition2=====
 
* Dosing Information
 
:* Dosage
 
=====Condition3=====
 
* Dosing Information
 
:* Dosage
 
=====Condition4=====
 
* Dosing Information
 
:* Dosage
 
<!--Off-Label Use and Dosage (Adult)-->
 
<!--Guideline-Supported Use (Adult)-->
 
|offLabelAdultGuideSupport=
 
=====Condition1=====
 
* Developed by:
 
* Class of Recommendation:
 
* Strength of Evidence:
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
 
<!--Non–Guideline-Supported Use (Adult)-->
 
|offLabelAdultNoGuideSupport=
 
=====Condition1=====
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
 
<!--Pediatric Indications and Dosage-->
 
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
 
|fdaLIADPed=
 
=====Condition1=====
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.
 
<!--Off-Label Use and Dosage (Pediatric)-->
 
<!--Guideline-Supported Use (Pediatric)-->
 
|offLabelPedGuideSupport=
 
=====Condition1=====
 
* Developed by:
 
* Class of Recommendation:
 
* Strength of Evidence:
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
 
<!--Non–Guideline-Supported Use (Pediatric)-->
 
|offLabelPedNoGuideSupport=
 
=====Condition1=====
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
 
<!--Contraindications-->
 
|contraindications=
 
* Condition1
 
<!--Warnings-->
 
|warnings=
 
* Description
 
====Precautions====
 
* Description
 
<!--Adverse Reactions-->
 
<!--Clinical Trials Experience-->
 
|clinicalTrials=
 
There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
 
=====Body as a Whole=====
 
 
 
 
=====Cardiovascular=====
 
 
 
 
=====Digestive=====
 
 
 
 
=====Endocrine=====
 
 
 
 
=====Hematologic and Lymphatic=====
 
 
 
 
=====Metabolic and Nutritional=====
 
 
 
 
=====Musculoskeletal=====
 
 
 
 
=====Neurologic=====
 
 
 
 
=====Respiratory=====
 
 
 
 
=====Skin and Hypersensitivy Reactions=====
 
 
 
 
=====Special Senses=====
 
 
 
 
=====Urogenital=====
 
 
 
 
=====Miscellaneous=====
 
 
 
<!--Postmarketing Experience-->
 
|postmarketing=
 
There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
 
=====Body as a Whole=====
 
 
 
=====Cardiovascular=====
 
 
 
=====Digestive=====
 
 
 
=====Endocrine=====
 
 
 
=====Hematologic and Lymphatic=====
 
 
 
=====Metabolic and Nutritional=====
 
 
 
=====Musculoskeletal=====
 
 
 
=====Neurologic=====
 
 
 
=====Respiratory=====
 
 
 
=====Skin and Hypersensitivy Reactions=====
 
 
 
=====Special Senses=====
 
 
 
=====Urogenital=====
 
 
 
=====Miscellaneous=====
 
 
 
<!--Drug Interactions-->
 
|drugInteractions=
 
* Drug
:* Description
 
<!--Use in Specific Populations-->
 
|useInPregnancyFDA=
* '''Pregnancy Category'''
 
|useInPregnancyAUS=
* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
 
|useInLaborDelivery=
There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
 
|useInNursing=
There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
 
|useInPed=
There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
 
|useInGeri=
There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
 
|useInGender=
There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
 
|useInRace=
There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
 
|useInRenalImpair=
There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
 
|useInHepaticImpair=
There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
 
|useInReproPotential=
There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
 
|useInImmunocomp=
There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
 
<!--Administration and Monitoring-->
 
|administration=
 
* Oral
 
* Intravenous
 
|monitoring=
 
There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
 
* Description
 
<!--IV Compatibility-->
 
|IVCompat=
 
There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
 
<!--Overdosage-->
 
|overdose=
 
===Acute Overdose===
 
====Signs and Symptoms====
 
* Description
 
====Management====
 
* Description
 
===Chronic Overdose===
 
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
 
<!--Pharmacology-->
 
<!--Drug box 2-->
 
|drugBox=
 
 
 
<!--Mechanism of Action-->
 
|mechAction=
 
* Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystis activity. The mechanism of action against Pneumocystis jiroveci has not been fully elucidated. In Plasmodium species, the site of action appears to be the cytochrome bc1 complex (Complex III). Several metabolic enzymes are linked to the mitochondrial electron transport chain via ubiquinone. Inhibition of electron transport by atovaquone will result in indirect inhibition of these enzymes. The ultimate metabolic effects of such blockade may include inhibition of nucleic acid and ATP synthesis.
 
<!--Structure-->
 
|structure=
 
* Atovaquone is an antiprotozoal agent. The chemical name of atovaquone is trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Atovaquone is a yellow crystalline solid that is practically insoluble in water. It has a molecular weight of 366.84 and the molecular formula C22H19ClO3. The compound has the following structural formula:
 
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
 
*Atovaquone Suspension is a formulation of micro-fine particles of atovaquone.
 
*The atovaquone particles, reduced in size to facilitate absorption, are significantly smaller than those in the previously marketed tablet formulation. Atovaquone Suspension is for oral administration and is bright yellow with a citrus flavor. Each teaspoonful (5 mL) contains 750 mg of atovaquone and the inactive ingredients benzyl alcohol, flavor (ethanol, propylene glycol, triacetin), poloxamer 188, purified water, saccharin sodium and xanthan gum.
 
<!--Pharmacodynamics-->
 
|PD=
 
There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.
 
<!--Pharmacokinetics-->
 
|PK=
 
*Absorption
:*Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone is highly dependent on formulation and diet. The suspension formulation provides an approximately 2-fold increase in atovaquone bioavailability in the fasting or fed state compared to the previously marketed tablet formulation. The absolute bioavailability of a 750-mg dose of Atovaquone Suspension administered under fed conditions in 9 HIV-infected (CD4 >100 cells/mm3) volunteers was 47% ± 15%. In the same study, the bioavailability of a 750-mg dose of the previously marketed tablet formulation was 23% ± 11%.
:*Administering atovaquone with food enhances its absorption by approximately 2 fold. In one study, 16 healthy volunteers received a single dose of 750 mg Atovaquone Suspension after an overnight fast and following a standard breakfast (23 g fat: 610 kCal). The mean (±SD) area under the concentration-time curve (AUC) values were 324 ± 115 and 801 ± 320 hr●mcg/mL under fasting and fed conditions, respectively, representing a 2.6 ± 1-fold increase. The effect of food (23 g fat: 400 kCal) on plasma atovaquone concentrations was also evaluated in a multiple-dose, randomized, crossover study in 19 HIV-infected volunteers (CD4 <200 cells/mm3) receiving daily doses of 500 mg Atovaquone Suspension. AUC was 280 ± 114 hr●mcg/mL when atovaquone was administered with food as compared to 169 ± 77 hr●mcg/mL under fasting conditions. Maximum plasma atovaquone concentration (Cmax) was 15.1 ± 6.1 and 8.8 ± 3.7 mcg/mL when atovaquone was administered with food and under fasting conditions, respectively.
 
*Dose Proportionality
:*Plasma atovaquone concentrations do not increase proportionally with dose. When Atovaquone Suspension was administered with food at dosage regimens of 500 mg once daily, 750 mg once daily and 1,000 mg once daily, average steady-state plasma atovaquone concentrations were 11.7 ± 4.8, 12.5 ± 5.8 and 13.5 ± 5.1 mcg/mL, respectively. The corresponding Cmax concentrations were 15.1 ± 6.1, 15.3 ± 7.6 and 16.8 ± 6.4 mcg/mL. When Atovaquone Suspension was administered to 5 HIV-infected volunteers at a dose of 750 mg twice daily, the average steady-state plasma atovaquone concentration was 21 ± 4.9 mcg/mL and Cmax was 24 ± 5.7 mcg/mL. The minimum plasma atovaquone concentration (Cmin) associated with the 750-mg twice-daily regimen was 16.7 ± 4.6 mcg/mL.
 
*Distribution
:*Following the intravenous administration of atovaquone, the volume of distribution at steady-state (Vdss) 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-infected children who received 750 mg atovaquone as the tablet formulation 4 times daily for 2 weeks, the cerebrospinal fluid concentrations of atovaquone were 0.04, 0.14 and 0.26 mcg/mL, representing less than 1% of the plasma concentration.
 
*Elimination
:* The plasma clearance of atovaquone following intravenous (IV) administration in 9 HIV-infected volunteers was 10.4 ± 5.5 mL/min (0.15 ± 0.09 mL/min/kg). The half-life of atovaquone was 62.5 ± 35.3 hours after IV administration and ranged from 67 ± 33.4 to 77.6 ± 23.1 hours across studies following administration of Atovaquone Suspension. The half-life of atovaquone is long due to presumed enterohepatic cycling and eventual fecal elimination. In a study where 14C-labelled atovaquone was administered to healthy volunteers, greater than 94% of the dose was recovered as unchanged atovaquone in the feces over 21 days. There was little or no excretion of atovaquone in the urine (less than 0.6%). There is indirect evidence that atovaquone may undergo limited metabolism; however, a specific metabolite has not been identified.
 
*Special Populations
 
*Pediatrics
:*In a study of Atovaquone Suspension in 27 HIV-infected, asymptomatic infants and children between 1 month and 13 years of age, the pharmacokinetics of atovaquone were age dependent. These patients were dosed once daily with food for 12 days. The average steady-state plasma atovaquone concentrations in the 24 patients with available concentration data are shown in Table 1.
 
T1
 
 
 
<!--Nonclinical Toxicology-->
 
|nonClinToxic=
 
There is limited information regarding <i>Nonclinical Toxicology</i> of {{PAGENAME}} in the drug label.
 
<!--Clinical Studies-->
 
|clinicalStudies=
 
There is limited information regarding <i>Clinical Studies</i> of {{PAGENAME}} in the drug label.
 
<!--How Supplied-->
 
|howSupplied=
 
*
 
<!--Patient Counseling Information-->
 
|fdaPatientInfo=
 
There is limited information regarding <i>Patient Counseling Information</i> of {{PAGENAME}} in the drug label.
 
<!--Precautions with Alcohol-->
 
|alcohol=
 
* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
 
<!--Brand Names-->
 
|brandNames=
 
* ®<ref>{{Cite web | title =  | url =  }}</ref>
 
<!--Look-Alike Drug Names-->
 
|lookAlike=
 
* A® — B®<ref name="www.ismp.org">{{Cite web  | last =  | first =  | title = http://www.ismp.org | url = http://www.ismp.org | publisher =  | date =  }}</ref>
 
<!--Drug Shortage Status-->
 
|drugShortage=
}}
 
<!--Pill Image-->
 
{{PillImage
|fileName=No image.jpg|This image is provided by the National Library of Medicine.
|drugName=
|NDC=
|drugAuthor=
|ingredients=
|pillImprint=
|dosageValue=
|dosageUnit=
|pillColor=
|pillShape=
|pillSize=
|pillScore=
}}
 
<!--Label Display Image-->
 
{{LabelImage
|fileName={{PAGENAME}}11.png|This image is provided by the National Library of Medicine.
}}
 
{{LabelImage
|fileName={{PAGENAME}}11.png|This image is provided by the National Library of Medicine.
}}
 
<!--Category-->
 
[[Category:Drug]]

Revision as of 20:25, 22 January 2015

Atovaquone
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]

Disclaimer

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Overview

Atovaquone is a that is FDA approved for the {{{indicationType}}} of . Common adverse reactions include .

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Condition1
  • Dosing Information
  • Dosage
Condition2
  • Dosing Information
  • Dosage
Condition3
  • Dosing Information
  • Dosage
Condition4
  • Dosing Information
  • Dosage

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition1
  • Developed by:
  • Class of Recommendation:
  • Strength of Evidence:
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Atovaquone in adult patients.

Non–Guideline-Supported Use

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Atovaquone in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding FDA-Labeled Use of Atovaquone in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition1
  • Developed by:
  • Class of Recommendation:
  • Strength of Evidence:
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Atovaquone in pediatric patients.

Non–Guideline-Supported Use

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Atovaquone in pediatric patients.

Contraindications

  • Condition1

Warnings

  • Description

Precautions

  • Description

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Atovaquone in the drug label.

Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Atovaquone in the drug label.

Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous

Drug Interactions

  • Drug
  • Description

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy Category


Pregnancy Category (AUS):

  • Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Atovaquone in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Atovaquone during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Atovaquone with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Atovaquone with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Atovaquone with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Atovaquone with respect to specific gender populations.

Race

There is no FDA guidance on the use of Atovaquone with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Atovaquone in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Atovaquone in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Atovaquone in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Atovaquone in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Oral
  • Intravenous

Monitoring

There is limited information regarding Monitoring of Atovaquone in the drug label.

  • Description

IV Compatibility

There is limited information regarding IV Compatibility of Atovaquone in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

  • Description

Management

  • Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Atovaquone in the drug label.

Pharmacology

There is limited information regarding Atovaquone Pharmacology in the drug label.

Mechanism of Action

  • Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystis activity. The mechanism of action against Pneumocystis jiroveci has not been fully elucidated. In Plasmodium species, the site of action appears to be the cytochrome bc1 complex (Complex III). Several metabolic enzymes are linked to the mitochondrial electron transport chain via ubiquinone. Inhibition of electron transport by atovaquone will result in indirect inhibition of these enzymes. The ultimate metabolic effects of such blockade may include inhibition of nucleic acid and ATP synthesis.

Structure

  • Atovaquone is an antiprotozoal agent. The chemical name of atovaquone is trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Atovaquone is a yellow crystalline solid that is practically insoluble in water. It has a molecular weight of 366.84 and the molecular formula C22H19ClO3. The compound has the following structural formula:
This image is provided by the National Library of Medicine.
  • Atovaquone Suspension is a formulation of micro-fine particles of atovaquone.
  • The atovaquone particles, reduced in size to facilitate absorption, are significantly smaller than those in the previously marketed tablet formulation. Atovaquone Suspension is for oral administration and is bright yellow with a citrus flavor. Each teaspoonful (5 mL) contains 750 mg of atovaquone and the inactive ingredients benzyl alcohol, flavor (ethanol, propylene glycol, triacetin), poloxamer 188, purified water, saccharin sodium and xanthan gum.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Atovaquone in the drug label.

Pharmacokinetics

  • Absorption
  • Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone is highly dependent on formulation and diet. The suspension formulation provides an approximately 2-fold increase in atovaquone bioavailability in the fasting or fed state compared to the previously marketed tablet formulation. The absolute bioavailability of a 750-mg dose of Atovaquone Suspension administered under fed conditions in 9 HIV-infected (CD4 >100 cells/mm3) volunteers was 47% ± 15%. In the same study, the bioavailability of a 750-mg dose of the previously marketed tablet formulation was 23% ± 11%.
  • Administering atovaquone with food enhances its absorption by approximately 2 fold. In one study, 16 healthy volunteers received a single dose of 750 mg Atovaquone Suspension after an overnight fast and following a standard breakfast (23 g fat: 610 kCal). The mean (±SD) area under the concentration-time curve (AUC) values were 324 ± 115 and 801 ± 320 hr●mcg/mL under fasting and fed conditions, respectively, representing a 2.6 ± 1-fold increase. The effect of food (23 g fat: 400 kCal) on plasma atovaquone concentrations was also evaluated in a multiple-dose, randomized, crossover study in 19 HIV-infected volunteers (CD4 <200 cells/mm3) receiving daily doses of 500 mg Atovaquone Suspension. AUC was 280 ± 114 hr●mcg/mL when atovaquone was administered with food as compared to 169 ± 77 hr●mcg/mL under fasting conditions. Maximum plasma atovaquone concentration (Cmax) was 15.1 ± 6.1 and 8.8 ± 3.7 mcg/mL when atovaquone was administered with food and under fasting conditions, respectively.
  • Dose Proportionality
  • Plasma atovaquone concentrations do not increase proportionally with dose. When Atovaquone Suspension was administered with food at dosage regimens of 500 mg once daily, 750 mg once daily and 1,000 mg once daily, average steady-state plasma atovaquone concentrations were 11.7 ± 4.8, 12.5 ± 5.8 and 13.5 ± 5.1 mcg/mL, respectively. The corresponding Cmax concentrations were 15.1 ± 6.1, 15.3 ± 7.6 and 16.8 ± 6.4 mcg/mL. When Atovaquone Suspension was administered to 5 HIV-infected volunteers at a dose of 750 mg twice daily, the average steady-state plasma atovaquone concentration was 21 ± 4.9 mcg/mL and Cmax was 24 ± 5.7 mcg/mL. The minimum plasma atovaquone concentration (Cmin) associated with the 750-mg twice-daily regimen was 16.7 ± 4.6 mcg/mL.
  • Distribution
  • Following the intravenous administration of atovaquone, the volume of distribution at steady-state (Vdss) 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-infected children who received 750 mg atovaquone as the tablet formulation 4 times daily for 2 weeks, the cerebrospinal fluid concentrations of atovaquone were 0.04, 0.14 and 0.26 mcg/mL, representing less than 1% of the plasma concentration.
  • Elimination
  • The plasma clearance of atovaquone following intravenous (IV) administration in 9 HIV-infected volunteers was 10.4 ± 5.5 mL/min (0.15 ± 0.09 mL/min/kg). The half-life of atovaquone was 62.5 ± 35.3 hours after IV administration and ranged from 67 ± 33.4 to 77.6 ± 23.1 hours across studies following administration of Atovaquone Suspension. The half-life of atovaquone is long due to presumed enterohepatic cycling and eventual fecal elimination. In a study where 14C-labelled atovaquone was administered to healthy volunteers, greater than 94% of the dose was recovered as unchanged atovaquone in the feces over 21 days. There was little or no excretion of atovaquone in the urine (less than 0.6%). There is indirect evidence that atovaquone may undergo limited metabolism; however, a specific metabolite has not been identified.
  • Special Populations
  • Pediatrics
  • In a study of Atovaquone Suspension in 27 HIV-infected, asymptomatic infants and children between 1 month and 13 years of age, the pharmacokinetics of atovaquone were age dependent. These patients were dosed once daily with food for 12 days. The average steady-state plasma atovaquone concentrations in the 24 patients with available concentration data are shown in Table 1.

T1

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Atovaquone in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Atovaquone in the drug label.

How Supplied

Storage

There is limited information regarding Atovaquone Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Atovaquone in the drug label.

Precautions with Alcohol

  • Alcohol-Atovaquone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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