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Mepron (Atovaquone)
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Pharmacology
Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystis activity. The mechanism of action against P.carinii has not been fully elucidated.
Pharmacokinetics: The pharmacokinetics of atovaquone have been studied in healthy volunteers, HIV-infected adults with varying stages and manifestations of HIV infection and in immunocompromised children. The half-life of atovaquone is long (2to 3days) due to presumed enterohepatic cycling and eventual fecal elimination. There is no evidence that the drug is metabolized in man.
Atovaquone is extensively bound to plasma proteins (>99.9%).
The bioavailability of atovaquone is highly dependent on formulation and diet. The atovaquone oral suspension formulation, which has now replaced the atovaquone tablets, has atovaquone particles significantly smaller than those in the tablet formulation, and provides an approximately 2-fold increase in atovaquone bioavailability in the fasting or fed state compared to the tablet formulation studied under the same conditions. The bioavailability of the oral suspension can be increased approximately 2- to 3-fold when administered with meals. Fat has been shown to enhance absorption significantly.
During a multiple-dose study of 4 HIV-seropositive asymptomatic volunteers, the relative oral bioavailability of thetablet formulation decreased at doses above 750mg once daily with food.
In another multiple-dose escalation study conducted in AIDS patients, lack of dose proportionality was also demonstrated with thetablet formulation; however there was a modest increase in concentrations.
Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystis activity. The mechanism of action against P.carinii has not been fully elucidated.
Pharmacokinetics: The pharmacokinetics of atovaquone have been studied in healthy volunteers, HIV-infected adults with varying stages and manifestations of HIV infection and in immunocompromised children. The half-life of atovaquone is long (2to 3days) due to presumed enterohepatic cycling and eventual fecal elimination. There is no evidence that the drug is metabolized in man.
Atovaquone is extensively bound to plasma proteins (>99.9%).
The bioavailability of atovaquone is highly dependent on formulation and diet. The atovaquone oral suspension formulation, which has now replaced the atovaquone tablets, has atovaquone particles significantly smaller than those in the tablet formulation, and provides an approximately 2-fold increase in atovaquone bioavailability in the fasting or fed state compared to the tablet formulation studied under the same conditions. The bioavailability of the oral suspension can be increased approximately 2- to 3-fold when administered with meals. Fat has been shown to enhance absorption significantly.
During a multiple-dose study of 4 HIV-seropositive asymptomatic volunteers, the relative oral bioavailability of thetablet formulation decreased at doses above 750mg once daily with food.
In another multiple-dose escalation study conducted in AIDS patients, lack of dose proportionality was also demonstrated with thetablet formulation; however there was a modest increase in concentrations.
Indications
Atovaquone Is A Hydroxy-1,4-naphthoquinone, An Analog Of Ubiquinone, With Antipneumocystis Activity. The Mechanism Of Action Against P.carinii Has Not Been Fully Elucidated.
Pharmacokinetics: The Pharmacokinetics Of Atovaquone Have Been Studied In Healthy Volunteers, HIV-infected Adults With Varying Stages And Manifestations Of HIV Infection And In Immunocompromised Children. The Half-life Of Atovaquone Is Long (2to 3days) Due To Presumed Enterohepatic Cycling And Eventual Fecal Elimination. There Is No Evidence That The Drug Is Metabolized In Man.
Atovaquone Is Extensively Bound To Plasma Proteins (>99.9%).
The Bioavailability Of Atovaquone Is Highly Dependent On Formulation And Diet. The Atovaquone Oral Suspension Formulation, Which Has Now Replaced The Atovaquone Tablets, Has Atovaquone Particles Significantly Smaller Than Those In The Tablet Formulation, And Provides An Approximately 2-fold Increase In Atovaquone Bioavailability In The Fasting Or Fed State Compared To The Tablet Formulation Studied Under The Same Conditions. The Bioavailability Of The Oral Suspension Can Be Increased Approximately 2- To 3-fold When Administered With Meals. Fat Has Been Shown To Enhance Absorption Significantly.
During A Multiple-dose Study Of 4 HIV-seropositive Asymptomatic Volunteers, The Relative Oral Bioavailability Of Thetablet Formulation Decreased At Doses Above 750mg Once Daily With Food.
In Another Multiple-dose Escalation Study Conducted In AIDS Patients, Lack Of Dose Proportionality Was Also Demonstrated With Thetablet Formulation; However There Was A Modest Increase In Concentrations.
Atovaquone Is A Hydroxy-1,4-naphthoquinone, An Analog Of Ubiquinone, With Antipneumocystis Activity. The Mechanism Of Action Against P.carinii Has Not Been Fully Elucidated.
Pharmacokinetics: The Pharmacokinetics Of Atovaquone Have Been Studied In Healthy Volunteers, HIV-infected Adults With Varying Stages And Manifestations Of HIV Infection And In Immunocompromised Children. The Half-life Of Atovaquone Is Long (2to 3days) Due To Presumed Enterohepatic Cycling And Eventual Fecal Elimination. There Is No Evidence That The Drug Is Metabolized In Man.
Atovaquone Is Extensively Bound To Plasma Proteins (>99.9%).
The Bioavailability Of Atovaquone Is Highly Dependent On Formulation And Diet. The Atovaquone Oral Suspension Formulation, Which Has Now Replaced The Atovaquone Tablets, Has Atovaquone Particles Significantly Smaller Than Those In The Tablet Formulation, And Provides An Approximately 2-fold Increase In Atovaquone Bioavailability In The Fasting Or Fed State Compared To The Tablet Formulation Studied Under The Same Conditions. The Bioavailability Of The Oral Suspension Can Be Increased Approximately 2- To 3-fold When Administered With Meals. Fat Has Been Shown To Enhance Absorption Significantly.
During A Multiple-dose Study Of 4 HIV-seropositive Asymptomatic Volunteers, The Relative Oral Bioavailability Of Thetablet Formulation Decreased At Doses Above 750mg Once Daily With Food.
In Another Multiple-dose Escalation Study Conducted In AIDS Patients, Lack Of Dose Proportionality Was Also Demonstrated With Thetablet Formulation; However There Was A Modest Increase In Concentrations.
Contraindications
Patients who develop, or have history of, potentially life-threatening allergic reactions to any of the components of the formulation.
Patients who develop, or have history of, potentially life-threatening allergic reactions to any of the components of the formulation.
Safety Information / Warning
Clinical experience with atovaquone has been limited to patients with mild to moderate PCP [(A a)DO 2 £45mmHg]. Treatment of more severe episodes of PCP has not been systematically studied with this agent. Also, the efficacy of atovaquone tablets in patients who are failing therapy with TMP-SMX has not been systematically studied and, therefore, cannot be recommended. Atovaquone has not been evaluated as an agent for PCP prophylaxis.
Clinical experience with atovaquone has been limited to patients with mild to moderate PCP [(A a)DO 2 £45mmHg]. Treatment of more severe episodes of PCP has not been systematically studied with this agent. Also, the efficacy of atovaquone tablets in patients who are failing therapy with TMP-SMX has not been systematically studied and, therefore, cannot be recommended. Atovaquone has not been evaluated as an agent for PCP prophylaxis.
Precautions
General: Absorption of orally administered atovaquone is limited but can be significantly increased when the drug is taken with food. Atovaquone plasma concentrations have been shown to correlate with the likelihood of successful treatment and survival. Therefore, parenteral therapy with other agents should be considered for patients who have difficulty taking atovaquone with food (see Pharmacology). Gastrointestinal disorders may limit absorption of orally administered drugs. Patients with these disorders also may not achieve plasma concentrations of atovaquone associated with response to therapy in controlled trials.
Based upon the spectrum of in vitro antimicrobial activity, atovaquone is not effective therapy for concurrent pulmonary conditions such as bacterial, viral or fungal pneumonia or mycobacterial diseases. Clinical deterioration in patients may be due to other pathogens, as well as progressive PCP. All patients with acute PCP should be carefully evaluated for all other possible causes of pulmonary disease and treated with additional agents as appropriate.
Geriatrics: Atovaquone has not been systematically evaluated in patients greater than 65years of age. Caution should be exercised when treating elderly patients reflecting the greater frequency of decreased hepatic, renal and cardiac function in this population.
Infants and Young Children: There are no efficacy studies in children. Clinical experience with atovaquone in the pediatric population is limited to a pharmacokinetic and safety study. No children under 4months of age participated in the PhaseI trial.
Pregnancy: 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.
Lactation: It is not known whether atovaquone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when administering atovaquone to a nursing mother. In a rat study, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma.
Drug Interactions : Atovaquone is highly bound to plasma protein (>99.9%). Therefore, caution should be used when administering atovaquone concurrently with other highly plasma protein bound drugs with narrow therapeutic indices, as competition for binding sites may occur. The extent of plasma protein binding of atovaquone in human plasma is not affected by the presence of therapeutic concentrations of phenytoin (15µg/mL), nor is the binding of this drug affected by the presence of atovaquone.
Laboratory Tests: It is not known if atovaquone interferes with clinical laboratory tests or assay results.
Information for the Patient: The importance of taking the prescribed dose of atovaquone oral suspension should be stressed. Patients should be instructed to take their daily doses with meals, as the presence of food will significantly improve the absorption of the drug.
The oral suspension should be shaken gently before use.
General: Absorption of orally administered atovaquone is limited but can be significantly increased when the drug is taken with food. Atovaquone plasma concentrations have been shown to correlate with the likelihood of successful treatment and survival. Therefore, parenteral therapy with other agents should be considered for patients who have difficulty taking atovaquone with food (see Pharmacology). Gastrointestinal disorders may limit absorption of orally administered drugs. Patients with these disorders also may not achieve plasma concentrations of atovaquone associated with response to therapy in controlled trials.
Based upon the spectrum of in vitro antimicrobial activity, atovaquone is not effective therapy for concurrent pulmonary conditions such as bacterial, viral or fungal pneumonia or mycobacterial diseases. Clinical deterioration in patients may be due to other pathogens, as well as progressive PCP. All patients with acute PCP should be carefully evaluated for all other possible causes of pulmonary disease and treated with additional agents as appropriate.
Geriatrics: Atovaquone has not been systematically evaluated in patients greater than 65years of age. Caution should be exercised when treating elderly patients reflecting the greater frequency of decreased hepatic, renal and cardiac function in this population.
Infants and Young Children: There are no efficacy studies in children. Clinical experience with atovaquone in the pediatric population is limited to a pharmacokinetic and safety study. No children under 4months of age participated in the PhaseI trial.
Pregnancy: 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.
Lactation: It is not known whether atovaquone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when administering atovaquone to a nursing mother. In a rat study, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma.
Drug Interactions : Atovaquone is highly bound to plasma protein (>99.9%). Therefore, caution should be used when administering atovaquone concurrently with other highly plasma protein bound drugs with narrow therapeutic indices, as competition for binding sites may occur. The extent of plasma protein binding of atovaquone in human plasma is not affected by the presence of therapeutic concentrations of phenytoin (15µg/mL), nor is the binding of this drug affected by the presence of atovaquone.
Laboratory Tests: It is not known if atovaquone interferes with clinical laboratory tests or assay results.
Information for the Patient: The importance of taking the prescribed dose of atovaquone oral suspension should be stressed. Patients should be instructed to take their daily doses with meals, as the presence of food will significantly improve the absorption of the drug.
The oral suspension should be shaken gently before use.
Side Effects / Adverse Effects
Because many patients who participated in clinical trials with atovaquone tablets had complications of advanced HIV disease, it was often difficult to distinguish adverse events caused by the drug from those caused by underlying medical conditions. There were no life-threatening or fatal adverse experiences caused by atovaquone tablets.
Although an equal percentage of patients receiving atovaquone tablets and TMP-SMX reported at least 1adverse experience, more patients receiving TMP-SMX required discontinuation of therapy due to an adverse event. Nine percent of patients receiving atovaquone tablets were prematurely discontinued from therapy due to an adverse event, versus 24% of patients receiving TMP-SMX. Eight patients receiving atovaquone tablets had therapy discontinued due to development of rash. The majority of cases of rash among patients receiving atovaquone tablets were mild and did not require the discontinuation of dosing. The only other clinical adverse experience which led to premature discontinuation of atovaquone tablets dosing by more than 1patient was the development of vomiting (n=2). The most common adverse experience requiring discontinuation of dosing in the TMP-SMX group was rash (n=16).
Laboratory test abnormalities reported for ³5% of the study population during the treatment period are summarized in TableIV. Five patients treated with atovaquone tablets and 15patients treated with TMP-SMX had therapy prematurely discontinued due to elevations in ALT/AST. In general, patients treated with atovaquone tablets developed fewer abnormalities in measures of hepatocellular function (ALT, AST, alkaline phosphatase) or amylase values than patients treated with TMP-SMX.
However, only 7% of patients discontinued treatment with atovaquone tablets due to adverse events, while 41% of patients who received pentamidine discontinued treatment for this reason (p=<0.001). Of the 5patients who discontinued therapy with atovaquone, 3reported rash (4%). Rash was not severe in any patient. No other reason for discontinuation of atovaquone tablets was cited more than once. The most frequently cited reasons for discontinuation of pentamidine therapy were hypoglycemia (8patients [11%]) and vomiting (6patients [9%]).
Laboratory test abnormalities reported in ³5% of patients in the pentamidine comparative study are presented in TableVI. Laboratory abnormality was reported as the reason for discontinuation of treatment in 2of 73patients who received atovaquone tablets. One patient (1%) had elevated creatinine and BUN levels and one patient (1%) had elevated amylase levels. Laboratory abnormalities were the sole or contributing factor in 14patients who prematurely discontinued pentamidine therapy. In the 71patients who received pentamidine, laboratory parameters most frequently reported as reasons for discontinuation were hypoglycemia (11%), elevated creatinine levels (6%), and leukopenia (4%).
Because many patients who participated in clinical trials with atovaquone tablets had complications of advanced HIV disease, it was often difficult to distinguish adverse events caused by the drug from those caused by underlying medical conditions. There were no life-threatening or fatal adverse experiences caused by atovaquone tablets.
Although an equal percentage of patients receiving atovaquone tablets and TMP-SMX reported at least 1adverse experience, more patients receiving TMP-SMX required discontinuation of therapy due to an adverse event. Nine percent of patients receiving atovaquone tablets were prematurely discontinued from therapy due to an adverse event, versus 24% of patients receiving TMP-SMX. Eight patients receiving atovaquone tablets had therapy discontinued due to development of rash. The majority of cases of rash among patients receiving atovaquone tablets were mild and did not require the discontinuation of dosing. The only other clinical adverse experience which led to premature discontinuation of atovaquone tablets dosing by more than 1patient was the development of vomiting (n=2). The most common adverse experience requiring discontinuation of dosing in the TMP-SMX group was rash (n=16).
Laboratory test abnormalities reported for ³5% of the study population during the treatment period are summarized in TableIV. Five patients treated with atovaquone tablets and 15patients treated with TMP-SMX had therapy prematurely discontinued due to elevations in ALT/AST. In general, patients treated with atovaquone tablets developed fewer abnormalities in measures of hepatocellular function (ALT, AST, alkaline phosphatase) or amylase values than patients treated with TMP-SMX.
However, only 7% of patients discontinued treatment with atovaquone tablets due to adverse events, while 41% of patients who received pentamidine discontinued treatment for this reason (p=<0.001). Of the 5patients who discontinued therapy with atovaquone, 3reported rash (4%). Rash was not severe in any patient. No other reason for discontinuation of atovaquone tablets was cited more than once. The most frequently cited reasons for discontinuation of pentamidine therapy were hypoglycemia (8patients [11%]) and vomiting (6patients [9%]).
Laboratory test abnormalities reported in ³5% of patients in the pentamidine comparative study are presented in TableVI. Laboratory abnormality was reported as the reason for discontinuation of treatment in 2of 73patients who received atovaquone tablets. One patient (1%) had elevated creatinine and BUN levels and one patient (1%) had elevated amylase levels. Laboratory abnormalities were the sole or contributing factor in 14patients who prematurely discontinued pentamidine therapy. In the 71patients who received pentamidine, laboratory parameters most frequently reported as reasons for discontinuation were hypoglycemia (11%), elevated creatinine levels (6%), and leukopenia (4%).
Overdose
Symptoms and Treatment: There have been no reports of overdosage from the tablet or oral suspension administration of atovaquone.
Symptoms and Treatment: There have been no reports of overdosage from the tablet or oral suspension administration of atovaquone.
Recommended Dosage
Adults: The recommended oral dose is 750mg (5mL) administered with food twice a day (total daily dose 1500mg) for 21days.
Failure to administer with food may result in lower plasma concentrations and may limit response to therapy.
Adults: The recommended oral dose is 750mg (5mL) administered with food twice a day (total daily dose 1500mg) for 21days.
Failure to administer with food may result in lower plasma concentrations and may limit response to therapy.
Supplied / Packaging
Each 5mL of bright yellow suspension, with a sweet, fruity flavor, contains: atovaquone 750mg. Nonmedicinal ingredients: benzyl alcohol, flavor (tutti frutti), poloxamer188, purified water, saccharin sodium and xanthan gum. Bottles of 210mL with child resistant cap. Store at 15to 25°C. Keep in tight, light resistant containers. Do not freeze.
Each 5mL of bright yellow suspension, with a sweet, fruity flavor, contains: atovaquone 750mg. Nonmedicinal ingredients: benzyl alcohol, flavor (tutti frutti), poloxamer188, purified water, saccharin sodium and xanthan gum. Bottles of 210mL with child resistant cap. Store at 15to 25°C. Keep in tight, light resistant containers. Do not freeze.
