ATOVAQUONE AND PROGUANIL HYDROCHLORIDE- atovaquone and proguanil hydrochloride tablet, film coated
DESCRIPTION
Atovaquone and proguanil hydrochloride is fixed-dose combination of the antimalarial agents atovaquone and proguanil hydrochloride. The chemical name of atovaquone is trans -2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Atovaquone is yellow crystalline solid that is practically insoluble in water. It has molecular weight of 366.84 and the molecular formula C22 H19 ClO3
The chemical name of proguanil hydrochloride USP is 1-(4-chlorophenyl)-5-isopropyl-biguanide hydrochloride. Proguanil hydrochloride USP is white crystalline solid that is sparingly soluble in water. It has molecular weight of 290.22 and the molecular formula C11 H16 ClN5 ?HCl
Atovaquone and proguanil hydrochloride tablets are for oral administration. Each atovaquone and proguanil hydrochloride tablet contains 250 mg of atovaquone and 100 mg of proguanil hydrochloride USP. The inactive ingredients in the tablet are colloidal silicon dioxide, ferric oxide red, hypromellose 2910, low substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, poloxamer 188, povidone K30, polyethylene glycol 400, polyethylene glycol 8000, sodium starch glycolate, titanium dioxide.
Microbiology:
Mechanism of Action:
The constituents of atovaquone and proguanil hydrochloride interfere with different pathways involved in the biosynthesis of pyrimidines required for nucleic acid replication. Atovaquone is selective inhibitor of parasite mitochondrial electron transport. Proguanil hydrochloride primarily exerts its effect by means of the metabolite cycloguanil, dihydrofolate reductase inhibitor. Inhibition of dihydrofolate reductase in the malaria parasite disrupts deoxythymidylate synthesis
Drug Interactions:
There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose.
Concomitant treatment with tetracycline has been associated with approximately 40% reduction in plasma concentrations of atovaquone.
Concomitant treatment with metoclopramide has also been associated with decreased bioavailability of atovaquone.
Concomitant administration of rifampin or rifabutin is known to reduce atovaquone levels by approximately 50% and 34%, respectivel
Concomitant administration of atovaquone (750 mg BID with food for 14 days) and indinavir (800 mg TID without food for 14 days) did not result in any change in the steady-state AUC and Cmax of indinavir but resulted in decrease in the Ctrough of indinavir (23% decrease [90% CI 8%, 35%]). Caution should be exercised when prescribing atovaquone with indinavir due to the decrease in trough levels of indinavir.
Atovaquone is highly protein bound (>99%) but does not displace other highly protein-bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely Proguanil is metabolized primarily by CYP2C19. Potential pharmacokinetic interactions with other substrates or inhibitors of this pathway are unknown.
INDICATIONS AND USAGE
Prevention of Malaria:
Atovaquone and proguanil hydrochloride tablets are indicated for the prophylaxis of P. falciparum malaria, including in areas where chloroquine resistance has been reported
Treatment of Malaria:
Atovaquone and proguanil hydrochloride tablets are indicated for the treatment of acute, uncomplicated P. falciparum malaria. Atovaquone and proguanil hydrochloride tablets have been shown to be effective in regions where the drugs chloroquine, halofantrine, mefloquine, and amodiaquine may have unacceptable failure rates, presumably due to drug resistance.
PRECAUTIONS
General:
Atovaquone and proguanil hydrochloride has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria, including hyperparasitemia, pulmonary edema, or renal failure. Patients with severe malaria are not candidates for oral therap
info. for Patients:
Patients should be instructed:
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to take atovaquone and proguanil hydrochloride tablets at the same time each day with food or milky drink.
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to take repeat dose of atovaquone and proguanil hydrochloride if vomiting occurs within hour after dosing.
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to take dose as soon as possible if dose is missed, then return to their normal dosing schedule. However, if dose is skipped, the patient should not double the next dose.
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that rare serious adverse events such as hepatitis, severe skin reactions, neurological, and hematological events have been reported when atovaquone and proguanil hydrochloride was used for the prophylaxis or treatment of malaria.
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to consult healthcare professional regarding alternative forms of prophylaxis if prophylaxis with atovaquone and proguanil hydrochloride is prematurely discontinued for any reason.
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that protective clothing, insect repellants, and bednets are important components of malaria prophylaxis.
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that no chemoprophylactic regimen is 100% effective; therefore, patients should seek medical attention for any febrile illness that occurs during or after return from malaria-endemic area and inform their healthcare professional that they may have been exposed to malaria.
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that falciparum malaria carries higher risk of death and serious complications in pregnant women than in the general population. Pregnant women anticipating travel to malarious areas should discuss the risks and benefits of such travel with their physicians
Pregnancy Category C
DOSAGE AND ADMINISTRATION
The daily dose should be taken at the same time each day with food or milky drink. In the event of vomiting within hour after dosing, repeat dose should be taken.
Prevention of Malaria:
Prophylactic treatment with atovaquone and proguanil hydrochloride should be started or days before entering malaria-endemic area and continued daily during the stay and for days after return.
Adults:
One atovaquone and proguanil hydrochloride tablet (adult strength 250 mg atovaquone/100 mg proguanil hydrochloride) per day.
Treatment of Acute Malaria:
Adults:
Four Atovaquone and proguanil hydrochloride tablets (adult strength; total daily dose g atovaquone/400 mg proguanil hydrochloride) as single dose daily for consecutive days.
