atovaquone 250 MG / proguanil HCl 100 MG Oral Tablet
Generic Name: ATOVAQUONE AND PROGUANIL HYDROCHLORIDE
Brand Name: Atovaquone and Proguanil Hydrochloride
- Substance Name(s):
- ATOVAQUONE
- PROGUANIL HYDROCHLORIDE
DRUG INTERACTIONS
Drug Interactions Concomitant treatment with tetracycline has been associated with approximately a 40% reduction in plasma concentrations of atovaquone.
Parasitemia should be closely monitored in patients receiving tetracycline.
While antiemetics may be indicated for patients receiving atovaquone and proguanil hydrochloride, metoclopramide may reduce the bioavailability of atovaquone and should be used only if other antiemetics are not available.
Concomitant administration of rifampin or rifabutin is known to reduce atovaquone levels by approximately 50% and 34%, respectively.
The concomitant administration of atovaquone and proguanil hydrochloride and rifampin or rifabutin is not recommended.
Proguanil may potentiate the anticoagulant effect of warfarin and other coumarin-based anticoagulants.
The mechanism of this potential drug interaction has not been established.
Caution is advised when initiating or withdrawing malaria prophylaxis or treatment with atovaquone and proguanil hydrochloride in patients on continuous treatment with coumarin-based anticoagulants.
When these products are administered concomitantly, suitable coagulation tests should be closely monitored.
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.
Potential interactions between proguanil or cycloguanil and other drugs that are CYP2C19 substrates or inhibitors are unknown.
OVERDOSAGE
There is no information on overdoses of atovaquone and proguanil hydrochloride substantially higher than the doses recommended for treatment.
There is no known antidote for atovaquone, and it is currently unknown if atovaquone is dialyzable.
The median lethal dose is higher than the maximum oral dose tested in mice and rats (1,825 mg/kg/day).
Overdoses up to 31,500 mg of atovaquone have been reported.
In one such patient who also took an unspecified dose of dapsone, methemoglobinemia occurred.
Rash has also been reported after overdose.
Overdoses of proguanil hydrochloride as large as 1,500 mg have been followed by complete recovery, and doses as high as 700 mg twice daily have been taken for over 2 weeks without serious toxicity.
Adverse experiences occasionally associated with proguanil hydrochloride doses of 100 to 200 mg/day, such as epigastria discomfort and vomiting would be likely to occur with overdose.
There are also reports of reversible hair loss and scaling of the skin on the palms and/or soles, reversible aphthous ulceration, and hematologic side effects.
DESCRIPTION
Atovaquone and proguanil hydrochloride is a 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 a yellow crystalline solid that is practically insoluble in water.
It has a molecular weight of 366.84 and the molecular formula C22H19ClO3.
The compound has the following structural formula: The chemical name of proguanil hydrochloride USP is 1-(4-chlorophenyl)-5-isopropyl-biguanide hydrochloride.
Proguanil hydrochloride USP is a white crystalline solid that is sparingly soluble in water.
It has a molecular weight of 290.22 and the molecular formula C11H16ClN5•HCl.
The compound has the following structural formula: 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.
Chemical Structure – Atovaquone Chemical Structure – Proguanil
HOW SUPPLIED
Atovaquone and proguanil hydrochloride tablets, containing 250 mg atovaquone and 100 mg proguanil hydrochloride, are pinkish brown to brown colored, circular, biconvex beveled edge, film-coated tablets with ‘404’ debossed on one side and ‘G’ debossed on the other side.
Atovaquone and proguanil hydrochloride tablets 250 mg/100 mg NDC 42254-150-16 bottles of 16 NDC 42254-150-24 bottles of 24 Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature).
GERIATRIC USE
Geriatric Use Clinical studies of atovaquone and proguanil hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, the higher systemic exposure to cycloguanil (see CLINICAL PHARMACOLOGY: Special Populations: Geriatrics), and the greater frequency of concomitant disease or other drug therapy.
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 (see CLINICAL STUDIES).
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.
PEDIATRIC USE
Pediatric Use Treatment of Malaria: The efficacy and safety of atovaquone and proguanil hydrochloride for the treatment of malaria have been established in controlled studies involving pediatric patients weighing 5 kg or more (see CLINICAL STUDIES).
Safety and effectiveness have not been established in pediatric patients who weigh less than 5 kg.
Prophylaxis of Malaria: The efficacy and safety of atovaquone and proguanil hydrochloride have been established for the prophylaxis of malaria in controlled studies involving pediatric patients weighing 11 kg or more (see CLINICAL STUDIES).
Safety and effectiveness have not been established in pediatric patients who weigh less than 11 kg.
PREGNANCY
Pregnancy Pregnancy Category C.
Falciparum malaria carries a higher risk of morbidity and mortality in pregnant women than in the general population.
Maternal death and fetal loss are both known complications of falciparum malaria in pregnancy.
In pregnant women who must travel to malaria-endemic areas, personal protection against mosquito bites should always be employed (see Information for Patients) in addition to antimalarials.
Atovaquone was not teratogenic and did not cause reproductive toxicity in rats at maternal plasma concentrations up to 5 to 6.5 times the estimated human exposure during treatment of malaria.
Following single-dose administration of 14C-labeled atovaquone to pregnant rats, concentrations of radiolabel in rat fetuses were 18% (mid-gestation) and 60% (late gestation) of concurrent maternal plasma concentrations.
In rabbits, atovaquone caused maternal toxicity at plasma concentrations that were approximately 0.6 to 1.3 times the estimated human exposure during treatment of malaria.
Adverse fetal effects in rabbits, including decreased fetal body lengths and increased early resorptions and post-implantation losses, were observed only in the presence of maternal toxicity.
Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent maternal plasma concentrations.
A pre- and post-natal study in Sprague-Dawley rats revealed no adverse effects at doses up to 16 mg/kg/day of proguanil hydrochloride (up to 0.2-times the average human exposure based on AUC comparisons.) Pre- and post-natal studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted.
The combination of atovaquone and proguanil hydrochloride was not teratogenic in rats at plasma concentrations up to 1.7 and 0.10 times, respectively, the estimated human exposure during treatment of malaria.
In rabbits, the combination of atovaquone and proguanil hydrochloride was not teratogenic or embryotoxic to rabbit fetuses at plasma concentrations up to 0.34 and 0.82 times, respectively, the estimated human exposure during treatment of malaria.
While there are no adequate and well-controlled studies of atovaquone and/or proguanil hydrochloride in pregnant women, atovaquone and proguanil hydrochloride may be used if the potential benefit justifies the potential risk to the fetus.
The proguanil component of atovaquone and proguanil hydrochloride acts by inhibiting the parasitic dihydrofolate reductase (see CLINICAL PHARMACOLOGY: Microbiology: Mechanism of Action).
However, there are no clinical data indicating that folate supplementation diminishes drug efficacy, and for women of childbearing age receiving folate supplements to prevent neural tube birth defects, such supplements may be continued while taking atovaquone and proguanil hydrochloride.
NUSRING MOTHERS
Nursing Mothers It is not known whether atovaquone is excreted into human milk.
In a rat study, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma.
Proguanil is excreted into human milk in small quantities.
Caution should be exercised when atovaquone and proguanil hydrochloride is administered to a nursing mother.
INFORMATION FOR PATIENTS
Information for Patients Patients should be instructed: to take atovaquone and proguanil hydrochloride tablets at the same time each day with food or a milky drink.
to take a repeat dose of atovaquone and proguanil hydrochloride if vomiting occurs within 1 hour after dosing.
to take a dose as soon as possible if a dose is missed, then return to their normal dosing schedule.
However, if a dose is skipped, the patient should not double the next dose.
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.
to consult a healthcare professional regarding alternative forms of prophylaxis if prophylaxis with atovaquone and proguanil hydrochloride is prematurely discontinued for any reason.
that protective clothing, insect repellants, and bednets are important components of malaria prophylaxis.
that no chemoprophylactic regimen is 100% effective; therefore, patients should seek medical attention for any febrile illness that occurs during or after return from a malaria-endemic area and inform their healthcare professional that they may have been exposed to malaria.
that falciparum malaria carries a 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 (see Pregnancy section).
DOSAGE AND ADMINISTRATION
The daily dose should be taken at the same time each day with food or a milky drink.
In the event of vomiting within 1 hour after dosing, a repeat dose should be taken.
Prevention of Malaria: Prophylactic treatment with atovaquone and proguanil hydrochloride should be started 1 or 2 days before entering a malaria-endemic area and continued daily during the stay and for 7 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 1 g atovaquone/400 mg proguanil hydrochloride) as a single dose daily for 3 consecutive days.
Patients with Renal Impairment: Atovaquone and proguanil hydrochloride tablet should not be used for malaria prophylaxis in patients with severe renal impairment (creatinine clearance <30 mL/min).
Atovaquone and proguanil hydrochloride tablet may be used with caution for the treatment of malaria in patients with severe renal impairment (creatinine clearance <30 mL/min), only if the benefits of the 3-day treatment regimen outweigh the potential risks associated with increased drug exposure (see CLINICAL PHARMACOLOGY: Special Populations: Renal Impairment).
No dosage adjustments are needed in patients with mild (creatinine clearance 50 to 80 mL/min) and moderate (creatinine clearance 30 to 50 mL/min) renal impairment (see CLINICAL PHARMACOLOGY: Special Populations).
Patients with Hepatic Impairment: No dosage adjustments are needed in patients with mild to moderate hepatic impairment.
No studies have been conducted in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY: Special Populations: Hepatic Impairment).