Action And Clinical 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 has 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 (2 to 3 days) 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, provides an approximately two-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 two- to three-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 the tablet formulation decreased at doses above 750 mg once daily with food.
In another multiple-dose escalation study conducted in AIDS patients, lack of dose proportionality was also demonstrated with the tablet formulation; however there was a modest increase in concentrations.
Indications And Clinical Uses: For the acute oral treatment of mild to moderate P. carinii pneumonia (PCP) in patients who are intolerant to trimethoprim-sulfamethoxazole (TMP-SMX).
The efficacy of atovaquone in patients who are failing therapy with TMP-SMX, has not been systematically studied (see Warnings).
The indication is based on the results of a comparative pharmacokinetic studies of the oral suspension and tablet formulations and clinical efficacy studies of the tablet formulation which established a relationship between atovaquone plasma concentration and successful treatment. The results of a randomized double-blind trial comparing atovaquone tablets to TMP-SMX in AIDS patients with mild to moderate PCP (defined as an alveolar-arterial oxygen diffusion gradient [(A-a)DO2] £45 mmHg and PaO2 ³60 mmHg on room air); and a randomized trial comparing atovaquone tablets and i.v. pentamidine isethionate in patients with mild to moderate PCP intolerant to trimethoprim or sulfa-antimicrobials. These studies are summarized below:
TMP-SMX Comparative Study: This double-blind trial initiated in 1990 was designed to compare the safety and efficacy of atovaquone tablets to that of TMP-SMX for the treatment of AIDS patients with histologically confirmed PCP. Only patients with mild to moderate PCP were eligible for enrollment.
A total of 408 patients were enrolled into the trial at 37 study centres. Eighty-six patients without histologic confirmation of PCP were excluded from the efficacy analyses. Of the 322 patients with histologically confirmed PCP, 160 were randomized to receive atovaquone tablets and 162 to TMP-SMX.
Study participants randomized to atovaquone treatment were to receive 750 mg atovaquone (three 250 mg tablets) 3 times daily for 21 days and those randomized to trimethoprim-sulfamethoxazole were to receive 320 mg TMP plus 1 600 mg SMX 3 times daily for 21 days.
All patients were evaluated for their response to treatment. Each patient was classified as a therapy success or failure. Therapy success was defined as improvement in clinical and respiratory measures persisting at least 4 weeks after cessation of therapy. Therapy failures included lack of response, treatment discontinuation due to an adverse experience, and unevaluable.
There was a significant difference (p=0.03) in mortality rates between the treatment groups. Among the 322 patients with confirmed PCP, 13 of 160 patients treated with atovaquone tablets and 4 of 162 patients receiving TMP-SMX died during the 21-day treatment course or an 8-week follow-up period. In the intent-to-treat analysis for all 408 randomized patients there were 16 deaths in the atovaquone tablets arm and 7 in the TMP-SMX arm (p=0.051).
This difference in mortality between the 2 treatment groups appeared to be partially due to a disproportionate number of fatal bacterial infections in the atovaquone tablets group. Four of the 13 atovaquone tablets-treated patients died of PCP, tablets while 5 of the 13 died of a combination of bacterial infections and PCP. A correlation between plasma concentrations and death was demonstrated; in general, patients with lower atovaquone plasma concentrations were more likely to die than patients with higher atovaquone plasma concentrations.
Sixty-two percent (62%) of patients on atovaquone tablets and 64% of patients on TMP-SMX were classified as protocol-defined therapy successes.
The failure rate due to lack of response was significantly larger for patients receiving atovaquone tablets, while the failure rate due to adverse experiences was larger for patients receiving TMP-SMX.
There were no significant differences in the effect of either treatment on additional indicators of response (i.e., arterial blood gas measurements, vital signs, serum LDH levels, clinical symptoms, and chest radiographs).
Pentamidine Comparative Study: This open, randomized trial initiated in 1991, was designed to compare the safety and efficacy of atovaquone tablets to that of pentamidine for the treatment of histologically confirmed mild or moderate PCP among AIDS patients. Approximately 80% of the patients had a history of, or were currently experiencing, intolerance to trimethoprim or sulfa-antimicrobials.
Patients randomized to atovaquone were to receive 750 mg atovaquone (three 250 mg tablets) 3 times daily for 21 days, and those randomized to pentamidine isethionate were to receive a 3 to 4 mg/kg single i.v. infusion daily for 21 days.
It was anticipated that patients intolerant of TMP-SMX would present in either of 2 ways. They would either have a known intolerance and would represent a primary therapy group, or their intolerance would first become evident during treatment for the current episode of PCP and would represent a study group for salvage therapy.
A total of 135 PCP-positive patients were enrolled: 110 were in the primary therapy group and 25 were in the salvage therapy group.
There was no difference in mortality rates between the treatment groups. Among the 135 patients with confirmed PCP, 10 of 70 patients treated with atovaquone tablets and 9 of 65 patients treated with pentamidine died during the 21-day treatment course or an 8-week follow-up period. Three of the 10 patients treated with atovaquone tablets died of PCP while another 3 patients died with a combination of bacterial infections and PCP. The contribution of PCP in these latter deaths is unclear. One patient died of sepsis, 1 died of lymphoma, 1 died of complications of AIDS and 1 died of refractory pneumothorax. Two of 9 patients treated with pentamidine died of PCP while another 3 patients died with a combination of bacterial infections and PCP. The contribution of PCP in these latter deaths is unclear. One each died of a cerebral mycotic aneurysm and disseminated C. immitis and 2 patients died of complications of AIDS. In the intent-to-treat analysis for all randomized patients, there were 11 deaths in the atovaquone tablets arm and 12 deaths in the pentamidine arm. For those patients for whom day 4 atovaquone plasma concentration are available, 3 of 5 (60%) patients with concentrations 5 g/mL died.
Data on Chronic Use: Atovaquone oral suspension has not been systematically evaluated as a chronic suppressive agent to prevent the development of PCP in patients at high risk for P. carinii disease. In a pilot-dosing study of chronic dosing of atovaquone tablets in AIDS patients, 5 of 31 patients had PCP breakthroughs: one patient at a dose of 750 mg once daily (after 20 days), three patients at 750 mg twice daily (after 14, 70, and 97 days), and one patient at 1500 mg twice daily (after 74 days). The dose used in the acute treatment studies (750 mg 3 times daily) was not studied and, therefore, there are no data on the rate of breakthrough at this dose. Based on these limited observations, no recommendation can be made as to the use of atovaquone oral suspension for prophylaxis.
Contra-Indications: Patients who develop, or have history of, potentially life-threatening allergic reactions to any of the components of the formulation.
Manufacturers’ Warnings In Clinical States: Clinical experience with atovaquone has been limited to patients with mild to moderate PCP [(A-a)DO2 Â£45 mmHg]. 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 65 years 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 4 months of age participated in the Phase I 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 (15 Âµg/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 test 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.
Adverse Reactions: 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 1 adverse 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 1 patient 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 5% of the study population during the treatment period are summarized in Table IV. Five patients treated with atovaquone tablets and 15 patients 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.
Table V summarizes the clinical adverse experiences reported by Â³5% of the study population during the comparative trial of atovaquone tablets and i.v. pentamidine (n=144), regardless of attribution. A slightly lower percentage of patients who received atovaquone tablets reported occurrence of adverse events than did those who received pentamidine (63% vs 72%).
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. Laboratory abnormality was reported as the reason for discontinuation of treatment in 2 of 73 patients 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 14 patients who prematurely discontinued pentamidine therapy. In the 71 patients who received pentamidine, laboratory parameters most frequently reported as reasons for discontinuation were hypoglycemia (11%), elevated creatinine levels (6%), and leukopenia (4%).
Symptoms And Treatment Of Overdose: Symptoms and Treatment: There have been no reports of overdosage from the tablet or oral suspension administration of atovaquone.
Dosage And Administration: Adults: The recommended oral dose is 750 mg (5 mL) administered with food twice a day (total daily dose 1 500 mg) for 21 days.
Failure to administer with food may result in lower plasma concentrations and may limit response to therapy.
Availability And Storage: Each 5 mL of bright yellow suspension, with a sweet, fruity flavor, contains: atovaquone 750 mg. Nonmedicinal ingredients: benzyl alcohol, flavor (tutti frutti), poloxamer 188, purified water, saccharin sodium and xanthan gum. Bottles of 210 mL with child resistant cap. Store at 15 to 25°C. Keep in tight, light resistant containers. Do not freeze.
MEPRON® Glaxo Wellcome Atovaquone Antiprotozoal Agent
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