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ATOVAQUONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Atovaquone, an analog of ubiquinone, is a hydroxy-1,4-naphthoquinone antiprotozoal agent. It has activity against a broad range of protozoa such as Plasmodium spp, Toxoplasma gondii, and Pneumocystis carinii.

Specific Substances

    1) 2-[trans -4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,-4-naphthoquinone
    2) 566C
    3) 566C80
    4) BW-566C
    5) BW-A566C
    6) BW-566C80
    7) Molecular Formula: C22-H19-O3-Cl
    8) CAS 95233-18-4

Available Forms Sources

    A) FORMS
    1) Atovaquone is available as 750 mg/5 mL oral suspension (Prod Info MEPRON(R) oral suspension, 2013).
    2) In the United States, atovaquone is available in combination with proguanil as 250 mg atovaquone/100 mg proguanil tablets and 62.5 mg atovaquone/25 mg proguanil pediatric tablets (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013; Prod Info MALARONE(R) oral tablets, 2008). Refer to "PROGUANIL" management for more information on proguanil toxicity.
    B) USES
    1) Atovaquone is indicated for the prevention and treatment of mild to moderate Pneumocystis carinii pneumonia (PCP) in patients 13 years of age and older who are intolerant to sulfamethoxazole/trimethoprim (Prod Info MEPRON(R) oral suspension, 2013).
    2) Atovaquone, in combination with proguanil, is an antimalarial agent indicated for the prophylaxis and treatment of acute, uncomplicated Plasmodium falciparum malaria, particularly in areas where chloroquine resistance has been reported (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013; Prod Info MALARONE(R) oral tablets, 2008). Refer to "PROGUANIL" management for more information on proguanil toxicity.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Atovaquone is indicated for the prevention and treatment of mild to moderate Pneumocystis carinii pneumonia (PCP) in patients 13 years of age and older who are intolerant to sulfamethoxazole/trimethoprim. Atovaquone, in combination with proguanil, is indicated for the prophylaxis and treatment of acute, uncomplicated Plasmodium falciparum malaria, particularly in areas where chloroquine resistance has been reported. Refer to "PROGUANIL" management for more information on proguanil toxicity.
    B) PHARMACOLOGY: The mechanism of action of atovaquone has not been fully elucidated. Atovaquone, a hydroxynaphthoquinone, is a potent and selective inhibitor of the mitochondrial electron-transport chain at the site of the cytochrome bc-1 complex (complex III). It inhibits the activity of dihydro-orotate dehydrogenase, a key enzyme in pyrimidine production and stops the de novo synthesis of pyrimidines. Because protozoan cells synthesize pyrimidines only de novo, unlike human cells which salvage preformed pyrimidines, atovaquone demonstrates protozoacidal activity without undue human toxicity.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Atovaquone is generally well tolerated by most patients. The most frequent adverse effects are maculopapular rash, gastrointestinal symptoms (diarrhea, nausea, and vomiting), headache, and fever. Other effects have included abdominal pain, neutropenia, anemia, elevated liver transaminases, hyponatremia, anorexia, dyspepsia, constipation, taste perversion, oral candidiasis, elevation of serum amylase, elevations in serum creatinine and BUN, vortex keratopathy, conjunctivitis, insomnia, dizziness, anxiety, weakness, cough, sinusitis, rhinitis, hyperglycemia, and hypersensitivity reactions.
    2) ATOVAQUONE/PROGUANIL: The following adverse effects have been reported in patients receiving atovaquone in combination with proguanil: Skin rash, erythema multiforme, Stevens-Johnson syndrome, photosensitivity, pruritus, nausea, vomiting, diarrhea, abdominal pain, anorexia, stomatitis, anorexia, neutropenia, anemia, hepatitis and fatal liver failure, cholestasis, hypersensitivity reactions, anaphylaxis, dizziness, asthenia, and cough.
    E) WITH POISONING/EXPOSURE
    1) Overdose data is limited. Overdoses up to 31.5 grams have produced minimal effects. Transient sinus dysrhythmia and maculopapular rash on the trunk and extremities have been reported in overdose patients.
    0.2.20) REPRODUCTIVE
    A) Atovaquone is classified as FDA pregnancy category C. Atovaquone/proguanil is classified as FDA pregnancy category C. No teratogenic effects or reproductive toxicity were observed in rats. Maternal toxicity was noted in rabbits at approximately one-half the therapeutic human dose.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs in symptomatic patients.
    C) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Monitor blood glucose in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Manage mild hypotension with IV fluids. For hyperglycemia, insulin therapy might be required. Monitor blood glucose.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.
    E) ANTIDOTES
    1) None.
    F) HYPERGLYCEMIA
    1) Insulin therapy might be required. Monitor blood glucose.
    G) ENHANCED ELIMINATION
    1) There is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of atovaquone from plasma. However, these procedures are unlikely to be of benefit due to the high protein binding of atovaquone.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    J) PHARMACOKINETICS
    1) Tmax: 8 hours. Absorption: Atovaquone is poorly absorbed from the GI tract following oral administration. Bioavailability is 23% to 47%. Protein binding: 99.9%. Vd: 0.6 L/kg. Excretion: Less than 0.6% of an atovaquone dose was excreted unchanged in the urine. Approximately 94% of a dose has been excreted in the feces over 21 days.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause hypotension, hyperglycemia, and hepatotoxicity.

Range Of Toxicity

    A) TOXICITY: A minimum toxic dose has not been established. Overdoses up to 31.5 grams have been well tolerated. ATOVAQUONE THERAPEUTIC DOSE: Adults and children older than 13 years of age: 750 mg (5 mL) orally twice daily for 21 days or 1500 mg (10 mL) once a day. ATOVAQUONE/PROGUANIL THERAPEUTIC DOSE: Adults: atovaquone 250 mg/proguanil 100 mg orally once daily 1 to 2 days prior to entering endemic area during stay, and for 7 days after return. Children: Varies with weight.

Clinical Effects

Summary Of Exposure

    A) USES: Atovaquone is indicated for the prevention and treatment of mild to moderate Pneumocystis carinii pneumonia (PCP) in patients 13 years of age and older who are intolerant to sulfamethoxazole/trimethoprim. Atovaquone, in combination with proguanil, is indicated for the prophylaxis and treatment of acute, uncomplicated Plasmodium falciparum malaria, particularly in areas where chloroquine resistance has been reported. Refer to "PROGUANIL" management for more information on proguanil toxicity.
    B) PHARMACOLOGY: The mechanism of action of atovaquone has not been fully elucidated. Atovaquone, a hydroxynaphthoquinone, is a potent and selective inhibitor of the mitochondrial electron-transport chain at the site of the cytochrome bc-1 complex (complex III). It inhibits the activity of dihydro-orotate dehydrogenase, a key enzyme in pyrimidine production and stops the de novo synthesis of pyrimidines. Because protozoan cells synthesize pyrimidines only de novo, unlike human cells which salvage preformed pyrimidines, atovaquone demonstrates protozoacidal activity without undue human toxicity.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Atovaquone is generally well tolerated by most patients. The most frequent adverse effects are maculopapular rash, gastrointestinal symptoms (diarrhea, nausea, and vomiting), headache, and fever. Other effects have included abdominal pain, neutropenia, anemia, elevated liver transaminases, hyponatremia, anorexia, dyspepsia, constipation, taste perversion, oral candidiasis, elevation of serum amylase, elevations in serum creatinine and BUN, vortex keratopathy, conjunctivitis, insomnia, dizziness, anxiety, weakness, cough, sinusitis, rhinitis, hyperglycemia, and hypersensitivity reactions.
    2) ATOVAQUONE/PROGUANIL: The following adverse effects have been reported in patients receiving atovaquone in combination with proguanil: Skin rash, erythema multiforme, Stevens-Johnson syndrome, photosensitivity, pruritus, nausea, vomiting, diarrhea, abdominal pain, anorexia, stomatitis, anorexia, neutropenia, anemia, hepatitis and fatal liver failure, cholestasis, hypersensitivity reactions, anaphylaxis, dizziness, asthenia, and cough.
    E) WITH POISONING/EXPOSURE
    1) Overdose data is limited. Overdoses up to 31.5 grams have produced minimal effects. Transient sinus dysrhythmia and maculopapular rash on the trunk and extremities have been reported in overdose patients.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever has been reported in up to 40% of patients following therapeutic administration of atovaquone (Prod Info MEPRON(R) oral suspension, 2015; Hughes et al, 1993; Chan et al, 1999; Falloon et al, 1991).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Vortex keratopathy and conjunctivitis have been reported (Shah et al, 1995; Kovacs, 1992).
    a) VORTEX KERATOPATHY: A 45-year-old man with AIDS and pulmonary Pneumocystis carinii developed bilateral vortex keratopathy involving the corneal epithelium after taking 750 mg of atovaquone three times daily for four weeks. It is suggested that the condition was due to lipophilic properties of atovaquone (Shah et al, 1995).
    b) CONJUNCTIVITIS: An AIDS patient receiving atovaquone 750 mg four times daily developed a blistering rash after 8 days of treatment. The drug was discontinued. On later resumption of therapy, conjunctivitis developed after 8 days (Kovacs, 1992).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) Transient sinus dysrhythmia was reported in 2 patients with AIDS taking up to 12 tablets (3000 mg) of atovaquone once daily (Hughes et al, 1991).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) In clinical trials, cough, sinusitis, and rhinitis occurred in up to 14%, 7%, and 24% of patients, respectively (Prod Info Mepron(R) suspension. Atovaquone, 1999). In another study, cough, rhinitis, and dyspnea occurred in approximately 25%, 20%, and 18% of patients, respectively (Chan et al, 1999).
    b) ATOVAQUONE/PROGUANIL: Cough was reported in 10% of pediatric patients receiving atovaquone/proguanil for malaria prophylaxis (n=330) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In clinical trials, headache and insomnia occurred in up to 18% and 19% of patients, respectively (Prod Info MEPRON(R) oral suspension, 2015). In another study, approximately 30% of patients taking atovaquone 750 mg/day to 1500 mg/day experienced headache (Chan et al, 1999).
    b) CASE REPORT: Frontal headaches were reported in a patient taking 750 mg of atovaquone 3 times daily for Pneumocystis carinii pneumonia. Although the treatment was not stopped, symptoms cleared (Epstein et al, 1994).
    c) ATOVAQUONE/PROGUANIL: Headache was reported in 10% of adult patients receiving atovaquone/proguanil for the treatment of malaria in 7 controlled trials (n=436) and in 13% of pediatric patients receiving atovaquone/proguanil (n=330) for malaria prophylaxis (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In clinical trials dizziness has been reported in 3% to 8% of patients receiving atovaquone (Prod Info Mepron(R) suspension. Atovaquone, 1999).
    b) ATOVAQUONE/PROGUANIL: Dizziness was reported in 5% of adult patients receiving atovaquone/proguanil for the treatment of malaria in 7 controlled studies (n=436) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    C) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Weakness has been reported in 8% of patients (Prod Info Mepron(R) suspension. Atovaquone, 1999).
    b) ATOVAQUONE/PROGUANIL: Asthenia was reported in 8% of adult patients receiving atovaquone/proguanil for the treatment of malaria in 7 controlled trials (n=436) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    D) ANXIETY
    1) WITH THERAPEUTIC USE
    a) Anxiety has been reported in 7% of patients (Prod Info Mepron(R) suspension. Atovaquone, 1999).
    E) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Bilateral lower leg paresthesias, frontal headaches, and loose stools were reported in a patient taking 750 milligrams of atovaquone three times daily for Pneumocystis carinii pneumonia. Although the treatment was continued, the paresthesias improved, and headache and diarrhea resolved with the end of treatment (Epstein et al, 1994).
    F) DEMENTIA
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Dementia was reported in 1 of 73 patients with AIDS receiving atovaquone in one case series (Dohn et al, 1994).
    G) SEIZURE
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, seizures and psychotic events, such as hallucinations, have been rarely reported with atovaquone/proguanil therapy; however, a causal relationship has not been established (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have occurred in approximately 26% and 14% of patients, respectively (Prod Info MEPRON(R) oral suspension, 2015; Pearson et al, 1999; Shapiro et al, 1999; Hughes et al, 1993).
    b) CASE REPORTS: Severe nausea and pruritus requiring discontinuation of therapy occurred in one patient after 12 days of taking atovaquone 750 milligrams four times daily. In another patient, vomiting that required discontinuation of therapy occurred after 45 days of atovaquone 750 milligrams four times daily (Katlama et al, 1996).
    c) ATOVAQUONE/PROGUANIL: Nausea was reported in 12% of adult patients receiving atovaquone/proguanil for the treatment of malaria (n=436). Nausea was reported in less than 1% of pediatric patients (2 to 17 years old; n=110) who received atovaquone/proguanil compared with 7% of pediatric patients who received chloroquine/proguanil (n=111) for malaria treatment (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    d) ATOVAQUONE/PROGUANIL: For malaria prophylaxis, vomiting was reported in 5% of children receiving atovaquone/proguanil (n=330; age range, 4 to 14 years), compared with 3% of those receiving placebo. Vomiting was also reported in 10% of pediatric patients (weight 11 to 40 kg; n=116) and 12% of adolescent and adult patients receiving atovaquone/proguanil for the treatment of malaria (n=436) and in 13% of pediatric patients with no malaria symptoms who received atovaquone/proguanil for 3 days (n=319) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea was reported in up to 42% of patients with Pneumocystis carinii pneumonia who were treated with atovaquone (Hughes et al, 1993).
    b) CASE REPORT: Peripheral neuropathy, frontal headache, and diarrhea were reported in one patient taking 750 milligrams of atovaquone three times daily for Pneumocystis carinii pneumonia. Although the treatment was continued, the paresthesias improved, and headache and diarrhea resolved with the end of treatment (Epstein et al, 1994).
    c) ATOVAQUONE/PROGUANIL: Diarrhea was reported in 6% of pediatric patients (weight 5 to less than 11 kg; n=100) and in 8% of adult patients receiving atovaquone/proguanil for the treatment of malaria (n=436). Diarrhea and vomiting may become severe and persistent and affect the absorption of atovaquone/proguanil; therefore, alternative antimalarial therapy may be required (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In clinical trials, abdominal pain occurred in approximately 4% to 10% of patients (Prod Info MEPRON(R) oral suspension, 2013).
    b) In one study, a patient reported epigastric pain after starting atovaquone. Symptoms resolved upon discontinuation of the drug (Pearson et al, 1999).
    c) ATOVAQUONE/PROGUANIL: For malaria prophylaxis, abdominal pain was reported in 13% of pediatric patients (aged 4 to 14 years; n=330) receiving atovaquone/proguanil compared with 8% of patients receiving placebo. For malaria treatment, abdominal pain was reported in 17% of adolescent and adult patients receiving atovaquone/proguanil (n=436) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    D) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) In clinical trials, anorexia and dyspepsia occurred in 7% and 5% of patients, respectively (Prod Info MEPRON(R) oral suspension, 2013).
    b) ATOVAQUONE/PROGUANIL: Anorexia was reported in 5% of adolescent and adult patients receiving atovaquone/proguanil for the treatment of malaria (n=436) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    E) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation and taste perversion have occurred in approximately 3% of patients (Prod Info Mepron(R) suspension. Atovaquone, 1999; Hughes et al, 1993).
    F) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) In one study, one patient reported change in taste after starting atovaquone (Pearson et al, 1999). In clinical trials, taste perversion occurred in 5% of patients taking atovaquone (Prod Info Mepron(R) suspension. Atovaquone, 1999).
    G) SERUM AMYLASE RAISED
    1) WITH THERAPEUTIC USE
    a) Elevations in serum amylase have been reported in approximately 7% to 8% of patients (Prod Info Mepron(R) suspension. Atovaquone, 1999).
    b) Pancreatitis has been reported during post-approval use of atovaquone (Prod Info MEPRON(R) oral suspension, 2008).
    c) In one study, a patient developed mild pancreatitis which did not require cessation of treatment. However, this may have been related to concurrent alcohol use (Epstein et al, 1994).
    d) Elevated serum amylase was reported in 1 of 73 patients receiving the drug in one series (Dohn et al, 1994).
    H) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, stomatitis has been reported in patients receiving atovaquone/proguanil therapy (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevations in ALT, AST, and alkaline phosphatase have occurred in up to 8% of patients receiving atovaquone; (Prod Info MEPRON(R) oral suspension, 2015; Falloon et al, 1991).
    b) In one study, elevations in transaminase levels and erythematous rash occurred in two patients. Symptoms resolved upon discontinuation of atovaquone (Epstein et al, 1994).
    B) INFLAMMATORY DISEASE OF LIVER
    1) WITH THERAPEUTIC USE
    a) Cases of hepatitis and fatal liver failure have been reported (Prod Info MEPRON(R) oral suspension, 2015).
    b) ATOVAQUONE/PROGUANIL: In postmarketing surveillance, rare cases of hepatitis have been reported in patients receiving atovaquone/proguanil therapy. Hepatic failure requiring liver transplant has also been reported among patients receiving atovaquone/proguanil therapy (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    C) CHOLESTASIS
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, cholestasis has been reported in patients receiving atovaquone/proguanil therapy (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) Elevations in serum creatinine and blood urea nitrogen levels were reported in 1 of 73 patients receiving the drug in one series (Dohn et al, 1994).
    B) RENAL IMPAIRMENT
    1) WITH THERAPEUTIC USE
    a) Acute renal impairment has been reported during post-approval use of atovaquone (Prod Info MEPRON(R) oral suspension, 2008).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In clinical trials, neutropenia has been reported in approximately 6% of patients receiving atovaquone (Prod Info Mepron(R) suspension. Atovaquone, 1999; Goldfrank et al, 1998; Falloon et al, 1991).
    b) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, neutropenia has been reported in patients receiving atovaquone/proguanil (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    B) METHEMOGLOBINEMIA
    1) WITH POISONING/EXPOSURE
    a) Methemoglobinemia has been reported (Prod Info MEPRON(R) oral suspension, 2015).
    b) CASE REPORT: A 44-year-old man developed methemoglobinemia after taking 31,500 mg of atovaquone and an unknown quantity of dapsone (a known cause of methemoglobinemia) in a suicide attempt. The methemoglobinemia resolved after one day (Cheung, 1999).
    C) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In clinical trials, anemia has been reported in approximately 2% of patients receiving atovaquone (Prod Info Mepron(R) suspension. Atovaquone, 1999; Goldfrank et al, 1998; Falloon et al, 1991).
    b) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, anemia has been reported rarely in patients receiving atovaquone/proguanil (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    D) PANCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, pancytopenia has been reported in patients with severe renal impairment receiving proguanil (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash has been reported in approximately 23% of patients receiving atovaquone (Hughes et al, 1993; Pearson et al, 1999; Dohn et al, 1994; Falloon et al, 1991).
    b) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, skin rash and erythema multiforme have been reported in association with atovaquone/proguanil therapy (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    c) CASE REPORT: A patient with AIDS receiving atovaquone 750 mg four times daily developed a blistering rash after 8 days of treatment. Erythema multiforme requiring discontinuation of therapy occurred after 10 weeks of atovaquone therapy (Kovacs, 1992).
    d) CASE SERIES: Erythematous rash was reported in three patients taking atovaquone 750 mg 3 times daily for Pneumocystis carinii pneumonia. Symptoms resolved after discontinuation of treatment (Epstein et al, 1994).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Rash was reported in a patient taking 2250 mg atovaquone suspension twice daily (3 times the recommended dose) for 7 days (Cheung, 1999).
    b) Maculopapular rash on the trunk and extremities was reported in a patient with AIDS taking 12 tablets (3000 mg) of atovaquone once daily. Although the treatment was not stopped, symptoms resolved by day 16 (Hughes et al, 1991).
    B) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Stevens-Johnson syndrome has been reported during post-approval use of atovaquone when used as part of a multi-drug regimen (Prod Info MEPRON(R) oral suspension, 2013).
    b) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, Stevens-Johnson syndrome has been rarely reported in association with atovaquone/proguanil therapy (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    C) PHOTOSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, photosensitivity has been reported in association with atovaquone/proguanil therapy (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    D) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus has occurred in at least 10% patients (Prod Info MEPRON(R) oral suspension, 2013).
    b) Severe nausea and pruritus requiring discontinuation of therapy occurred in one patient after 12 days of atovaquone 750 mg four times daily (Katlama et al, 1996).
    c) ATOVAQUONE/PROGUANIL: Pruritus was reported in 6% of pediatric patients (weight 11 to 40 kg) receiving atovaquone/proguanil for the treatment of malaria (n=116) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) In clinical trials, muscle pain occurred in up to 10% of patients who received atovaquone (Prod Info MEPRON(R) oral suspension, 2015).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia were reported in 9% of patients, respectively (Prod Info MEPRON(R) oral suspension, 2013).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions have been reported with atovaquone (Prod Info MEPRON(R) oral suspension, 2015).
    b) ATOVAQUONE/PROGUANIL: Serious cases of allergic reaction, including angioedema, urticaria, and rare cases of anaphylaxis and vasculitis, have been reported with atovaquone/proguanil therapy during worldwide postmarketing surveillance (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    B) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, rare cases of anaphylaxis have been reported with atovaquone/proguanil therapy (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).

Reproductive

    3.20.1) SUMMARY
    A) Atovaquone is classified as FDA pregnancy category C. Atovaquone/proguanil is classified as FDA pregnancy category C. No teratogenic effects or reproductive toxicity were observed in rats. Maternal toxicity was noted in rabbits at approximately one-half the therapeutic human dose.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) There was no significant association between atovaquone-proguanil use during early pregnancy (week 3 through week 8 and in the first trimester) and major birth defects in a retrospective cohort study of the Danish Medical Birth Register (n=570,877). Researchers cross-referenced prescription drug records and birth defect incidence (during a 1-year follow-up post birth) associated with live births recorded between January 2000 and September 2008 to find infants exposed to atovaquone-proguanil between 3 and 8 weeks' gestation (n=93) and during the first trimester (n=149). Within these cohorts, 1.1% (n=1) and 1.3% (n=2), respectively, of infants had major birth defects, yielding an adjusted prevalence odds ratio of 0.43 (95% confidence interval (CI), 0.06 to 3.11) and 0.55 (95% CI, 0.14 to 2.21) in the 3- to 8-weeks' gestation and first-trimester cohorts, respectively. Study limitations included a small number of exposed cases and the potential for bias in the results due to possible maternal noncompliance with the medication; furthermore, the analysis could only exclude a more than 3-times higher risk of birth defects with drug exposure (Pasternak & Hviid, 2011).
    B) ANIMAL STUDIES
    1) RATS: No teratogenic effects or reproductive toxicity were observed in rats at plasma concentrations up to two to three times the estimated therapeutic human dose (Prod Info MEPRON(R) oral suspension, 2013). No teratogenicity or reproductive toxicity were observed in a pre- and post-natal study in rats administered maternal doses up to 1000 mg/kg/day (approximately 7.3 times the estimated human exposure during treatment of malaria based on AUC) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    2) RABBITS: Maternal toxicity was noted in rabbits at plasma concentrations approximately one-half the estimated therapeutic human dose (Prod Info MEPRON(R) oral suspension, 2013). Adverse fetal effects and maternal toxicity were observed in rabbits at a dose of 1200 mg/kg/day (approximately 1.3 times the estimated human exposure during treatment of malaria based on AUC) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified atovaquone as FDA pregnancy category C (Prod Info MEPRON(R) oral suspension, 2013). Atovaquone/proguanil is classified as FDA pregnancy category C (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    2) Atovaquone should only be used during pregnancy if the potential benefit outweighs the potential fetal risk (Prod Info MEPRON(R) oral suspension, 2013).
    B) ANIMAL STUDIES
    1) RABBITS: Atovaquone concentrations in rabbit fetuses averaged 30% of the maternal plasma concentrations. Higher levels of reabsorption and post-implantation losses were reported, as well as decreases in average body weight and length in rabbit fetuses (Prod Info MEPRON(R) oral suspension, 2013). Adverse fetal effects, including decreased body lengths, increased early resorptions, and increased post-implantation losses, were observed in rabbits at a maternally toxic dose of 1200 mg/kg/day (approximately 1.3 times the estimated human exposure during treatment of malaria based on AUC) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    2) RATS: No teratogenic effects or reproductive toxicity were observed in rats at plasma concentrations up to two to three times the estimated therapeutic human dose.(Prod Info MEPRON(R) oral suspension, 2013). No adverse effects in offspring were observed in a pre- and post-natal study in rats administered maternal doses up to 1000 mg/kg/day (approximately 7.3 times the estimated human exposure during treatment of malaria based on AUC) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013). When a single (14)C-radiolabelled dose was administered to rats, 18% and 60% of the maternal plasma concentration were transferred to rat fetuses during middle gestation and late gestation, respectively (Prod Info MEPRON(R) oral suspension, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether atovaquone is excreted in human milk. Exercise caution when administering to a pregnant woman (Prod Info MEPRON(R) oral suspension, 2013).
    B) ANIMAL STUDIES
    1) RATS: Atovaquone concentrations in the milk were 30% of the concentrations in the maternal plasma (Prod Info MEPRON(R) oral suspension, 2013).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) No fertility impairment was observed in male and female rats administered doses up to 1000 mg/kg/day (approximately 7.3 times the estimated human exposure during treatment of malaria based on AUC) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) HEPATIC CARCINOMA
    1) Studies in mice demonstrated increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested (1.4 to 3.6 times the average steady-state plasma concentrations in humans) (Prod Info Mepron(R) suspension. Atovaquone, 1999).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs in symptomatic patients.
    C) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Monitor blood glucose in symptomatic patients.

Methods

    A) CHROMATOGRAPHY
    1) Hughes et al (1991) described a high-pressure liquid chromatographic (HPLC) method for the determination of atovaquone in human plasma. The reported sensitivity of this method is 0.1 mcg/mL with an accuracy of 94.1% (Falloon et al, 1991).
    2) In another report, Hussein et al (1997) reported the use of a reversed-phase (C8) HPLC column and ultraviolet detection for quantification of atovaquone in human fluids. Lower limit of quantification was reported to be 0.1 mcg/mL (Hussein et al, 1997).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs in symptomatic patients.
    C) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Monitor blood glucose in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Manage mild hypotension with IV fluids. For hyperglycemia, insulin therapy might be required. Monitor blood glucose.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs in symptomatic patients.
    3) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    4) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    5) Monitor blood glucose in symptomatic patients.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) MYELOSUPPRESSION
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    2) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage.

Enhanced Elimination

    A) LACK OF INFORMATION
    1) There is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of atovaquone from plasma. However, these procedures are unlikely to be of benefit due to the high protein binding of atovaquone.
    B) MULTIPLE DOSE ACTIVATED CHARCOAL
    1) In theory multiple dose activated charcoal would be expected to increase systemic clearance of atovaquone, as it undergoes extensive enterohepatic recirculation, however the use of multiple dose activated charcoal after atovaquone ingestion has not been studied. Multiple dose charcoal is not routinely recommended because of the apparent low order of toxicity of atovaquone. It should only be considered in patients with severe toxicity not responding to supportive care.

Range Of Toxicity

Summary

    A) TOXICITY: A minimum toxic dose has not been established. Overdoses up to 31.5 grams have been well tolerated. ATOVAQUONE THERAPEUTIC DOSE: Adults and children older than 13 years of age: 750 mg (5 mL) orally twice daily for 21 days or 1500 mg (10 mL) once a day. ATOVAQUONE/PROGUANIL THERAPEUTIC DOSE: Adults: atovaquone 250 mg/proguanil 100 mg orally once daily 1 to 2 days prior to entering endemic area during stay, and for 7 days after return. Children: Varies with weight.

Therapeutic Dose

    7.2.1) ADULT
    A) MALARIA PROPHYLAXIS
    1) One tablet (atovaquone 250 mg/proguanil hydrochloride 100 mg) taken at the same time each day with a meal or milky drink (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    B) PCP PROPHYLAXIS
    1) The recommended dose is 1500 mg (10 mL) ORALLY administered once daily with food (Prod Info MEPRON(R) oral suspension, 2013).
    C) TREATMENT OF MALARIA
    1) The recommended dose is 4 tablets (atovaquone 1 g/proguanil hydrochloride 400 mg) taken as a single daily dose for 3 consecutive days (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    D) TREATMENT OF MILD TO MODERATE PCP
    1) The recommended dose is 750 mg (5 mL) ORALLY administered twice daily with food for 21 days (Prod Info MEPRON(R) oral suspension, 2013).
    7.2.2) PEDIATRIC
    A) MALARIA PROPHYLAXIS
    1) LESS THAN 11 KG: Safety and efficacy for prevention of malaria in pediatric patients weighing less than 11 kg have not been established (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    2) 11 TO 20 KG: The recommended dose is one pediatric tablet daily (atovaquone 62.5 mg/proguanil hydrochloride 25 mg) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    3) 21 TO 30 KG: The recommended dose is 2 pediatric tablets taken as a single dose daily (atovaquone 125 mg/proguanil hydrochloride 50 mg) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    4) 31 TO 40 KG: The recommended dose is 3 pediatric tablets taken as a single dose daily (atovaquone 187.5 mg/proguanil hydrochloride 75 mg) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    5) GREATER THAN 40 KG: The recommended dose is one ADULT tablet taken daily (atovaquone 250 mg/proguanil hydrochloride 100 mg) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    B) PCP PROPHYLAXIS
    1) ADOLESCENTS 13 TO 16 YEARS OF AGE: The recommended dose is 1500 mg (10 mL) ORALLY administered once daily with food (Prod Info MEPRON(R) oral suspension, 2013).
    C) TREATMENT OF MALARIA
    1) LESS THAN 5 KG: Safety and efficacy for treatment of malaria in pediatric patients weighing less than 5 kg have not been established (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    2) 5 TO 8 KG: The recommended dose is 2 pediatric tablets (atovaquone 125 mg/proguanil hydrochloride 50 mg) taken daily for 3 consecutive days (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    3) 9 TO 10 KG: The recommended dose is 3 pediatric tablets (atovaquone 187.5 mg/proguanil hydrochloride 75 mg) taken daily for 3 consecutive days (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    4) 11 TO 20 KG: The recommended dose is one ADULT tablet (atovaquone 250 mg/proguanil hydrochloride 100 mg) taken daily for 3 consecutive days (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    5) 21 TO 30 KG: The recommended dose is 2 ADULT tablets (atovaquone 500 mg/proguanil hydrochloride 200 mg) taken as a single dose daily for 3 consecutive days (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    6) 31 TO 40 KG: The recommended dose is 3 ADULT tablets (atovaquone 750 mg/proguanil hydrochloride 300 mg) taken as a single dose daily for 3 consecutive days (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    7) GREATER THAN 40 KG: The recommended dose is 4 ADULT tablets (atovaquone 1 g/proguanil hydrochloride 400 mg) taken as a single dose daily for 3 consecutive days (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    D) TREATMENT OF MILD TO MODERATE PCP
    1) ADOLESCENTS 13 TO 16 YEARS OF AGE: The recommended dose is 750 mg (5 mL) ORALLY administered twice daily with food for 21 days (Prod Info MEPRON(R) oral suspension, 2013).

Maximum Tolerated Exposure

    A) ADULT
    1) Overdoses up to 31.5 grams have been tolerated (Prod Info MEPRON(R) oral suspension, 2013).
    B) CASE REPORTS
    1) A 44-year-old AIDS patient reported no symptoms from the accidental ingestion of 9000 mg of atovaquone. Follow-up chemistries did not show any abnormalities. Atovaquone plasma concentrations at 48 and 66 hours post-overdose were 9.50 and 6.78 mcg/mL, respectively (approximately 3 times the expected plasma concentrations based on a single dose of oral suspension)(Cheung, 1999).
    2) Rash was reported in a patient taking 2250 mg atovaquone suspension twice daily (3 times the recommended dose) for 7 days (Cheung, 1999).
    3) A 44-year-old man developed methemoglobinemia after taking 15,500 mg of atovaquone and an unknown quantity of dapsone in a suicide attempt. Methemoglobinemia, a known toxic effect of dapsone, resolved after one day (Cheung, 1999).
    4) Severe nausea and pruritus requiring discontinuation of therapy occurred in one patient after 12 days of taking atovaquone 750 mg 4 times daily. In another patient, vomiting requiring discontinuation of therapy occurred after 45 days of atovaquone 750 mg 4 times daily (Katlama et al, 1996).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) ADULT
    a) The therapeutic plasma concentration range of atovaquone appears to be 10 to 20 micrograms/milliliter. In HIV-infected patients, the average steady-state plasma concentration after a dose of 750 milligrams twice daily was 21.0 +/- 4.9 micrograms/milliliter (Prod Info Mepron(R) suspension. Atovaquone, 1999).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The mechanism of action of atovaquone has not been fully elucidated. Atovaquone, a hydroxynaphthoquinone, is a potent and selective inhibitor of the mitochondrial electron-transport chain at the site of the cytochrome bc-1 complex (complex III). It inhibits the activity of dihydro-orotate dehydrogenase, a key enzyme in pyrimidine production and stops the de novo synthesis of pyrimidines. Because protozoan cells synthesize pyrimidines only de novo, unlike human cells which salvage preformed pyrimidines, atovaquone demonstrates protozoacidal activity without undue human toxicity (Artymowicz & James, 1993; Hughes et al, 1993; Prod Info Mepron(R) suspension. Atovaquone, 1999; Sattler & Feinberg, 1992).
    B) MINIMUM INHIBITORY CONCENTRATIONS - The in vitro 50% inhibitory concentration (IC50) of atovaquone against Pneumocystis carinii is approximately 0.1 to 3 micrograms/milliliter (Prod Info Mepron(R) suspension. Atovaquone, 1999).
    C) Atovaquone has activity against a broad range of protozoa such as Plasmodium spp, Toxoplasma gondii, and Pneumocystis carinii. Atovaquone is useful as second-line oral therapy of mild-to-moderate Pneumocystis carinii pneumonia (PCP) in immunocompromised patients intolerant of cotrimoxazole. It is also indicated for prophylaxis of P. carinii pneumonia in patients who cannot tolerate cotrimoxazole. It is also effective in the treatment of cerebral and ocular toxoplasmosis and malaria (especially in combination with proguanil) (Prod Info Mepron(R) suspension. Atovaquone, 1999; Reynolds, 2000).

Physicochemical

Physical Characteristics

    A) Atovaquone is a yellow crystalline solid that is insoluble in water (Prod Info Mepron(R) suspension. Atovaquone, 1999).

Molecular Weight

    A) 366.84 (Reynolds, 2000)

References

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    35) Product Information: MEPRON(R) oral suspension, atovaquone oral suspension. GlaxoSmithKline, Research Triangle Park, NC, 2008.
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