Mepron

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 (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 a highly lipophilic compound with a low aqueous solubility. It 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 atovaquone oral suspension can be increased greatly when administered with meals. In healthy volunteers, a standard meal (23 g fat; 610 kcal) increased the bioavailability 2- to 3-fold following 750 mg single doses of atovaquone suspension. The mean area under the atovaquone plasma concentration-time curve (AUC) was increased 2.5-fold and the mean C_max was increased 3.4-fold. Fat has been shown to enhance absorption significantly.

In healthy volunteers there is no evidence that the drug is metabolized and there is negligible excretion of atovaquone in the urine, with parent drug being predominantly (>90%) excreted unchanged in feces.

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; there was, however, a modest increase in concentrations.

As experience is limited, care should be taken when combining other drugs with atovaquone. 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 µg/mL). Atovaquone does not affect the pharmacokinetics, metabolism or extent of protein binding of phenytoin in vivo. In vitro there is no plasma protein binding interaction between atovaquone and quinine, phenytoin, warfarin, sulfamethoxazole, indomethacin or diazepam.

The concomitant administration of atovaquone and rifampin or rifabutin is not recommended. Concomitant administration of rifampin or rifabutin is known to reduce atovaquone levels by approximately 50% and 34%, respectively, and could result in subtherapeutic plasma concentrations in some patients.

Concomitant treatment with tetracycline or metoclopramide has been associated with significant decreases in plasma concentrations of atovaquone. Caution should be exercised in prescribing these drugs with atovaquone oral suspension until the potential interaction has been further studied.

In clinical trials of atovaquone oral suspension, small decreases in plasma concentrations of atovaquone (mean <3 µg/mL) were associated with concomitant administration of acetaminophen, benzodiazepines, acyclovir, opiates, cephalosporins, antidiarrheals and laxatives. The causal relationship between the change in plasma concentrations of atovaquone and the administration of these drugs is unknown.

Zidovudine does not appear to affect the pharmacokinetics of atovaquone. However, pharmacokinetic data have shown that atovaquone appears to decrease the rate of metabolism of zidovudine to its glucuronide metabolite (steady-state AUC of zidovudine was increased by 33% and peak plasma concentration of the glucuronide was decreased by 19%). At zidovudine dosages of 500 or 600 mg/day, it would seem unlikely that a 3-week, concomitant course of atovaquone oral suspension for the treatment of acute PCP would result in an increased incidence of adverse reactions attributable to higher plasma concentrations of zidovudine. Extra care should be taken in monitoring patients receiving prolonged atovaquone oral suspension therapy. There are no data available for ddC (zalcitabine).

Didanosine (ddI) does not affect the pharmacokinetics of atovaquone as determined in a prospective multidose drug interaction study of atovaquone and ddI. However, there was a 24% decrease in the AUC for ddI when coadministered with atovaquone which is unlikely to be of clinical significance.

Concomitant administration of atovaquone and indinavir results in a decrease in the C_min of indinavir (23% decrease; 90% CI 8 to 35%). Caution should be exercised when prescribing atovaquone with indinavir due to the decrease in trough levels of indinavir.

In clinical trials of atovaquone the following drugs were not associated with a change in steady state plasma concentrations of atovaquone: fluconazole, clotrimazole, ketoconazole, antacids, systemic corticosteroids, nonsteroidal anti-inflammatory drugs, antiemetics (excluding metoclopramide) and H₂-antagonists.

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.

There is no clinically significant change in the average rate or extent of absorption of atovaquone between elderly and young patients. A trend toward an increase in t_1/2 in elderly subjects after a single dose suggests that atovaquone may accumulate after multiple dosing.

It is not known whether atovaquone is excreted in human milk, and breast-feeding is not recommended. In a rat study, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma.

There are no efficacy studies in children. Clinical experience with atovaquone in immunosuppressed pediatric patients is limited to safety data from one pharmacokinetic study (n=11). No children under 4 months of age participated in the Phase I trial.

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. The prescriber must be aware that diarrhea at the start of treatment has been shown to be associated with significantly lower atovaquone plasma levels. These, in turn, are correlated with a higher incidence of therapy failures and a lower survival rate.

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.

Rare cases of hepatitis, elevated liver function tests, and one case of fatal liver failure have been reported in patients treated with atovaquone. A causal relationship between atovaquone use and these events could not be established because of numerous confounding medical conditions and concomitant drug therapies (see Adverse Effects, Post-Marketing Adverse Reactions).

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.

In patients with mild to moderate renal impairment, oral clearance and/or AUC data for atovaquone are within the range of values observed in patients with normal renal function. The C_max and AUC of total atovaquone (bound+free) are reduced in patients with severe renal impairment. The effect of severe renal impairment on free (unbound) concentrations of atovaquone in plasma is unknown.

In patients with mild to moderate hepatic impairment, there is no clinically significant change in exposure to atovaquone when compared to healthy patients. No data are available in patients with severe hepatic impairment.

Ability to Perform Tasks That Require Judgement, Motor or Cognitive skills: There have been no studies to investigate the effect of atovaquone on driving performance or the ability to operate machinery.

It is not known if atovaquone interferes with clinical laboratory tests or assay results.

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.

Patients should be informed that hypersensitivity (allergic) reactions have occurred with this product with symptoms such as hives, swelling of tissues (ie hands, feet, throat), tightening of the throat, and difficulty in breathing. Skin rash, which may blister and look like small targets (central dark spots surrounded by a paler area with a dark ring around the edge [erythema multiforme]) and widespread rash with blisters and peeling skin (particularly occurring around the mouth, nose, eyes and genitals [Stevens-Johnson Syndrome]) are also possible. Other reported events include inflammation of the liver or pancreas, decrease in kidney function, decrease of platelets in the blood, higher than normal level of methemoglobin (metHb) in the blood and deposits in the eye. Patients should contact a doctor, hospital emergency department or regional poison control centre immediately if any of these symptoms occur.

The oral suspension should be shaken gently before use.

vortex keratopathy.

Hepatitis and one case of fatal liver failure have been reported with atovaquone usage.

acute renal impairment.

methemoglobinemia, thrombocytopenia.

Erythema multiforme and Stevens-Johnson syndrome and skin desquamation have been reported in patients receiving multiple drug therapy including atovaquone.

hypersensitivity reactions including angioedema, bronchospasm, throat tightness and urticaria.

pancreatitis.

In addition to adverse events reported from clinical trials, the following events have been identified during worldwide post-approval use of atovaquone. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to atovaquone.

There is insufficient experience to predict the consequences of or suggest specific management of overdosage from the oral administration of atovaquone oral suspension. If overdosage occurs, the patient should be monitored and standard supportive treatment applied.

The recommended oral dose is 750 mg (5 mL) administered with food twice a day (total daily dose 1500 mg) for 21 days.

Failure to administer with food may result in lower plasma concentrations and may limit response to therapy (see Pharmacology and Precautions).