Atovaquone – Proguanil HCl
Action And Clinical Pharmacology: The constituents of Malarone, interfere with 2 different pathways involved in the biosynthesis of pyrimidines required for nucleic acid replication. Atovaquone is a selective inhibitor of parasite mitochondrial electron transport. Proguanil exerts its effect primarily by means of the metabolite cycloguanil, a dihydrofolate reductase inhibitor. Inhibition of dihydrofolate reductase in the malaria parasite disrupts deoxythymidylate synthesis. These two mechanisms are believed to be the prime explanation of the synergy observed when used in combination.
Pharmacokinetics: There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose.
The pharmacokinetics of atovaquone, proguanil and cycloguanil were characterized following daily oral administration of separate tablets of atovaquone and proguanil HCl in 9 children (meanÂ±SD of 9Â±2 years of age) for 3 consecutive days. Administration of tablets was based on mg/kg body weight basis.
The lower atovaquone AUC and Cmax values in Thai children compared to European adults is related to a higher clearance of atovaquone in children compared to adults. This is also shown by the 2-fold lower elimination half-life of atovaquone in children compared to adults. Atovaquone clearance is also higher in oriental adults compared to European adults.
Absorption: Atovaquone is a highly lipophilic compound with low aqueous solubility. Dietary fat taken with atovaquone increases the rate and extent of absorption. When taken with a standard breakfast containing 23 g of fat, AUC was increased 2 to 3 times and Cmax 5 times compared to the fasting state. Patients should take Malarone tablets with food (see Dosage).
Proguanil is rapidly and extensively absorbed regardless of food intake.
Distribution: Atovaquone is highly protein bound (>99%) but does not displace other highly protein bound drugs in vitro, indicating that significant drug interactions arising from displacement are unlikely. Proguanil is 75% protein bound. In human plasma the binding of atovaquone and proguanil were unaffected by the presence of the other.
Metabolism: There is no evidence that atovaquone is metabolized and there is negligible excretion of atovaquone in urine with the parent drug being predominantly (>90%) eliminated unchanged in feces.
Proguanil is partially metabolized with less than 40% being excreted unchanged in the urine. Its metabolites cycloguanil and 4-chlorophenylbiguanide are also excreted in the urine.
Elimination: The elimination half-life of atovaquone is about 2 to 3 days in adults and 1 to 2 days in children 6 to 12 years of age.
The elimination half-lives of proguanil and cycloguanil are about 12 to 15 hours in both adults and children 6 to 12 years of age.
Indications And Clinical Uses: For the treatment of acute, uncomplicated P. falciparum malaria when oral treatment is appropriate.
Malarone has been shown to be effective in areas where P. falciparum may be resistant to some other antimalarials.
The indication is based on 5 controlled clinical studies conducted in 466 patients (adults and children) receiving concurrent atovaquone and proguanil at the recommended dose (see Dosage). Most of the patients were residents of malaria endemic areas and may have had previous malaria infections that could have conferred a degree of immunity.
Contra-Indications: Individuals with known hypersensitivity to atovaquone or proguanil or any component of the formulation (see Supplied).
Manufacturers’ Warnings In Clinical States: Malarone has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria including hyperparasitemia, pulmonary edema or renal failure.
In the event of recrudescent infections due to P. falciparum, patients should be treated with a different antimalarial.
Because absorption of atovaquone may be reduced in patients with severe diarrhea, or gastrointestinal disorders, alternative therapy should be considered in such patients. However, if Malarone were to be used in these patients parasitemia should be closely monitored.
Parasitemia should be closely monitored in patients receiving concurrent rifampin or metoclopramide (see Precautions, Drug Interactions).
Precautions: General: Patients who have a history of epilepsy or psychiatric illness should take Malarone with caution (see Adverse Effects).
Absorption of orally administered atovaquone is significantly reduced when fasting. Therefore alternative therapy with other agents should be considered for patients who are not able to consume food.
Geriatrics: Since no studies have been carried out in the elderly, no special precautions or dosage adjustments can be recommended in this age group.
Pregnancy: There are no studies in pregnant women. Malarone should be considered for use in pregnancy only if the expected benefit to the mother justifies the potential risk to the fetus and mother.
There is no evidence of teratogenicity in animal reproductive studies with atovaquone alone. Studies in rats on proguanil alone or in combination with atovaquone show no evidence of teratogenic effects. However, animal studies are not always predictive of human response.
Lactation : It is not recommended that mothers receiving Malarone breast-feed their babies. It is not known whether atovaquone is excreted in human milk. Proguanil is excreted in human milk in small quantities. In a rat study, the atovaquone concentrations in milk were 30% of the concurrent atovaquone concentrations in maternal plasma.
The amount of atovaquone or proguanil found in human breast milk would not provide adequate treatment for the infant against malaria.
Children: Malarone is not recommended for treatment of children under 3 years of age.
Renal Impairment: Malarone has not been specifically studied in patients with renal impairment.
The lack of renal elimination of atovaquone implies that renal failure would have little effect on atovaquone elimination. Despite the known renal elimination of proguanil and cycloguanil, clinically significant accumulation is unlikely given the short duration of treatment. To date, no special precautions or dosage adjustment for patients with renal impairment have been identified.
Hepatic Impairment: Malarone has not been specifically studied in patients with hepatic impairment.
The metabolic route of elimination of proguanil is via the liver. Atovaquone elimination is substantially liver dependent. Clinically significant accumulation of proguanil and atovaquone is unlikely given the short duration of treatment. To date, no special precautions or dosage adjustment for patients with hepatic impairment have been identified.
Drug Interactions: Parasitemia should be closely monitored in patients receiving tetracycline, rifampin or metoclopramide concurrently with Malarone. Concomitant treatment with metoclopramide and rifampin have been associated with significant decreases in plasma concentrations of atovaquone. Increased clearance of atovaquone when coadministered with tetracycline, leading to 40% lower atovaquone concentrations has been observed.
Malarone should not be administered in combination with other antimalarial drugs. Interactions between Malarone and other antimalarial drugs have not been studied.
Atovaquone is highly protein bound (>99%) but does not displace other highly protein bound drugs in vitro, indicating that significant drug interactions arising from displacement are unlikely.
Adverse Reactions: As Malarone contains atovaquone and proguanil, the type and severity of adverse reactions associated with each of the compounds may be expected. The most common adverse experiences reported while receiving treatment with atovaquone are: rash, nausea, diarrhea, headache, vomiting, fever and insomnia. The most common adverse experiences reported while receiving treatment with proguanil are: anorexia, nausea, vomiting, abdominal pain, diarrhea, mouth ulcers, stomatitis and headache. At the doses employed for the treatment of malaria, adverse reactions have generally been mild and of limited duration. There has been no evidence of increased toxicity following concurrent administration of the two compounds.
Of the 7 severe or treatment limiting adverse experiences reported in clinical trials with atovaquone and proguanil, 3 were considered to be treatment related; two were reports of nausea and/or vomiting and 1, a report of an anaphylactic reaction. Two subjects receiving atovaquone/proguanil had seizures; in 1 of these cases the patient successfully continued treatment. Both subjects had a prior history of seizures and the investigators did not consider the events to be exacerbated by Malarone treatment. During clinical trials, 2 subjects receiving atovaquone monotherapy experienced psychiatric symptoms. One subject had a history of psychiatric illness and the other a history of drug and alcohol abuse. Studies of this size and design would only be able to detect adverse events at a rate of 1:150 (95% CI).
Table V provides a summary of the adverse events reported in clinical trials with Malarone tablets. Abdominal pain, headache, anorexia, nausea, vomiting, diarrhea and coughing were the most commonly reported adverse experiences.
A similar profile of clinical adverse events was reported in children with malaria treated with atovaquone and proguanil in phase III trials as occurred in the adult studies.
Abnormalities in liver function tests (elevated bilirubin and transaminases) were reversible and not associated with untoward clinical events.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: There have been no reports of overdosage with Malarone. In cases of suspected overdosage, symptomatic and supportive therapy should be given as appropriate.
Dosage And Administration: The daily dose should be taken with food or a milky drink at the same time each day (see Precautions). In the event of vomiting within 1 hour of dosing, a repeat dose should be taken. Should vomiting continue, alternative therapy should be considered or the patient’s parasitemia should be monitored.
Adults: 4 tablets as a single dose for 3 consecutive days.
Children (see Precautions, Children):
Clearance of atovaquone and proguanil following oral administration of Malarone is dependent on body weight. Although the Cmax and AUC for atovaquone and proguanil were lower in children than in adults, the clinical cure rates in children were comparable to those seen in adults.
SuppliedSupplied: Each pink, round biconvex film-coated tablet, branded GX CM3, contains: atovaquone 250 mg and proguanil base 85.6 mg (equivalent to proguanil HCl 100 mg). Nonmedicinal ingredients: low-substituted hydroxypropyl cellulose, macrogol 400, magnesium stearate, microcrystalline cellulose, poloxamer 188, polyethylene glycol, povidone K30, sodium starch glycollate; film-coating suspension (pink color concentrate OY-S-24972): macrogol 400, methylhydroxypropylcellulose, red iron oxide and titanium dioxide. Blister packs of 12. Store between 15 and 30Â°C.
MALARONE Glaxo Wellcome Atovaquone – Proguanil HCl Antimalarial