CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Atovaquone and proguanil hydrochloride tablets, fixed-dose combination of atovaquone and proguanil hydrochloride is an antimalarial agent [see Microbiology ( 12.4)] .

12.2 Pharmacodynamics

Cardiac Effects

The effect of atovaquone and proguanil hydrochloride on the QT interval is unknown in humans.

12.3 Pharmacokinetics

Absorption

Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone shows considerable inter-individual variability.

Effect of Food: Atovaquone and proguanil hydrochloride should be taken with food or a milky drink. Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC 2 to 3 times and C max 5 times over fasting. The absolute bioavailability of the tablet formulation of atovaquone when taken with food is 23%.

Distribution

Atovaquone is highly protein bound (> 99%) over the concentration range of 1 to 90 mcg/mL. A population pharmacokinetic analysis demonstrated that the apparent volume of distribution of atovaquone (V/F) in adult and pediatric patients after oral administration is approximately 8.8 L/kg.

Proguanil is 75% protein bound. A population pharmacokinetic analysis demonstrated that the apparent V/F of proguanil in adult and pediatric patients older than 15 years with body weights from 31 to 110 kg ranged from 1,617 to 2,502 L. In pediatric patients 15 years and younger with body weights from 11 to 56 kg, the V/F of proguanil ranged from 462 to 966 L.

In human plasma, the binding of atovaquone and proguanil was unaffected by the presence of the other.

Elimination

The elimination half-life of atovaquone is about 2 to 3 days in adult patients.

The elimination half-life of proguanil is 12 to 21 hours in both adult patients and pediatric patients, but may be longer in individuals who are slow metabolizers.

The main routes of elimination are hepatic biotransformation and renal excretion.

Metabolism: In a study where 14C-labeled atovaquone was administered to healthy volunteers, greater than 94% of the dose was recovered as unchanged atovaquone in the feces over 21 days. There was little or no excretion of atovaquone in the urine (less than 0.6%). There is indirect evidence that atovaquone may undergo limited metabolism; however, a specific metabolite has not been identified. Between 40% to 60% of proguanil is excreted by the kidneys. Proguanil is metabolized to cycloguanil (primarily via cytochrome P450 2C19 [CYP2C19]) and 4-chlorophenylbiguanide.

Excretion: A population pharmacokinetic analysis in adult and pediatric patients showed that the apparent clearance (CL/F) of both atovaquone and proguanil are related to body weight. The values CL/F for both atovaquone and proguanil in subjects with body weight ≥11 kg are shown in Table 4.

Table 4. Apparent Clearance for Atovaquone and Proguanil in Patients as a Function of Body Weight

a SD = Standard deviation.

The pharmacokinetics of atovaquone and proguanil in patients with body weight less than 11 kg have not been adequately characterized.

Specific Populations

Pediatric Patients: The pharmacokinetics of proguanil and cycloguanil are similar in adult patients and pediatric patients. However, the elimination half-life of atovaquone is shorter in pediatric patients (1 to 2 days) than in adult patients (2 to 3 days). In clinical trials, plasma trough concentrations of atovaquone and proguanil in pediatric patients weighing 5 to 40 kg were within the range observed in adults after dosing by body weight.

Geriatric Patients: In a single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 elderly subjects (aged 65 to 79 years) with those of 13 younger subjects (aged 30 to 45 years). In the elderly subjects, the extent of systemic exposure (AUC) of cycloguanil was increased (point estimate: 2.36, 90% Cl: 1.70, 3.28). T max was longer in elderly subjects (median 8 hours) compared with younger subjects (median: 4 hours) and average elimination half-life was longer in elderly subjects (mean: 14.9 hours) compared with younger subjects (mean: 8.3 hours).

Patients with Renal Impairment: In patients with mild renal impairment (creatinine clearance 50 to 80 mL/min), oral clearance and/or AUC data for atovaquone, proguanil, and cycloguanil are within the range of values observed in patients with normal renal function (creatinine clearance > 80 mL/min). In patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min), mean oral clearance for proguanil was reduced by approximately 35% compared with patients with normal renal function (creatinine clearance > 80 mL/min) and the oral clearance of atovaquone was comparable between patients with normal renal function and mild renal impairment. No data exist on the use of atovaquone and proguanil hydrochloride for long-term prophylaxis (over 2 months) in individuals with moderate renal failure. In patients with severe renal impairment (creatinine clearance < 30 mL/min), atovaquone C max and AUC are reduced but the elimination half-lives for proguanil and cycloguanil are prolonged, with corresponding increases in AUC, resulting in the potential of drug accumulation and toxicity with repeated dosing [see Contraindications ( 4)] .

Patients with Hepatic Impairment: In a single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 subjects with hepatic impairment (9 mild, 4 moderate, as indicated by the Child-Pugh method) with those of 13 subjects with normal hepatic function. In subjects with mild or moderate hepatic impairment as compared with healthy subjects, there were no marked differences (< 50%) in the rate or extent of systemic exposure of atovaquone. However, in subjects with moderate hepatic impairment, the elimination half-life of atovaquone was increased (point estimate: 1.28, 90% CI: 1 to 1.63). Proguanil AUC, C max, and its elimination half-life increased in subjects with mild hepatic impairment when compared with healthy subjects (Table 5). Also, the proguanil AUC and its elimination half-life increased in subjects with moderate hepatic impairment when compared with healthy subjects. Consistent with the increase in proguanil AUC, there were marked decreases in the systemic exposure of cycloguanil (C max and AUC) and an increase in its elimination half-life in subjects with mild hepatic impairment when compared with healthy volunteers (Table 5). There were few measurable cycloguanil concentrations in subjects with moderate hepatic impairment. The pharmacokinetics of atovaquone, proguanil, and cycloguanil after administration of atovaquone and proguanil hydrochloride have not been studied in patients with severe hepatic impairment.

Table 5. Point Estimates (90% CI) for Proguanil and Cycloguanil Parameters in Subjects with Mild and Moderate Hepatic Impairment Compared with Healthy Volunteers

ND = Not determined due to lack of quantifiable data.

a Ratio of geometric means.

b Mean difference.

Drug Interaction Studies

There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose.

Atovaquone is highly protein bound (> 99%) but does not displace other highly protein-bound drugs in vitro.

Proguanil is metabolized primarily by CYP2C19. Potential pharmacokinetic interactions between proguanil or cycloguanil and other drugs that are CYP2C19 substrates or inhibitors are unknown.

Rifampin/Rifabutin: Concomitant administration of rifampin or rifabutin is known to reduce atovaquone concentrations by approximately 50% and 34%, respectively. The mechanisms of these interactions are unknown.

Tetracycline: Concomitant treatment with tetracycline has been associated with approximately a 40% reduction in plasma concentrations of atovaquone.

Metoclopramide: Concomitant treatment with metoclopramide has been associated with decreased bioavailability of atovaquone.

Indinavir: Concomitant administration of atovaquone (750 mg twice daily with food for 14 days) and indinavir (800 mg three times daily without food for 14 days) did not result in any change in the steady-state AUC and C max of indinavir but resulted in a decrease in the C trough of indinavir (23% decrease [90% CI: 8%, 35%]).

12.4 Microbiology

Mechanism of Action

The constituents of atovaquone and proguanil hydrochloride tablets, atovaquone and proguanil hydrochloride, 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 hydrochloride primarily exerts its effect by means of the metabolite cycloguanil, a dihydrofolate reductase inhibitor. Inhibition of dihydrofolate reductase in the Plasmodium parasite disrupts deoxythymidylate synthesis.

Antimicrobial Activity

Atovaquone and cycloguanil (an active metabolite of proguanil) are active against the erythrocytic and exoerythrocytic stages of P. Falciparum. Enhanced efficacy of the combination compared with either atovaquone or proguanil hydrochloride alone was demonstrated in clinical trials in both immune and non-immune patients [see Clinical Studies ( 14.1, 14.2)] .

Resistance

Strains of P. falciparum with decreased susceptibility to atovaquone or proguanil/cycloguanil alone can be selected in vitro or in vivo. The combination of atovaquone and proguanil hydrochloride may not be effective for treatment of recrudescent malaria that develops after prior therapy with the combination.

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CONTRAINDICATIONS SECTION

Highlight: * Known serious hypersensitivity reactions to atovaquone or proguanil hydrochloride or any component of the formulation. ( 4)

• Prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance < 30 mL/min). ( 4)

4 CONTRAINDICATIONS

• Atovaquone and proguanil hydrochloride is contraindicated in individuals with known hypersensitivity reactions (e.g., anaphylaxis, erythema multiforme or Stevens-Johnson syndrome, angioedema, vasculitis) to atovaquone or proguanil hydrochloride or any component of the formulation.

• Atovaquone and proguanil hydrochloride is contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance < 30 mL/min) because of pancytopenia in patients with severe renal impairment treated with proguanil [see Use in Specific Populations ( 8.6), Clinical Pharmacology ( 12.3)].

WARNINGS AND PRECAUTIONS SECTION

Highlight: * Atovaquone absorption may be reduced in patients with diarrhea or vomiting. If used in patients who are vomiting, parasitemia should be closely monitored and the use of an antiemetic considered. In patients with severe or persistent diarrhea or vomiting, alternative antimalarial therapy may be required. ( 5.1)

• In mixed P. falciparum and Plasmodium vivax infection, P. vivax relapse occurred commonly when patients were treated with atovaquone and proguanil hydrochloride alone. ( 5.2)
• In the event of recrudescent P. falciparum infections after treatment or prophylaxis failure, patients should be treated with a different blood schizonticide. ( 5.2)
• Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use. ( 5.3)
• Atovaquone and proguanil hydrochloride has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria. Patients with severe malaria are not candidates for oral therapy. ( 5.4)

5 WARNINGS AND PRECAUTIONS

5.1 Vomiting and Diarrhea

Absorption of atovaquone may be reduced in patients with diarrhea or vomiting. If atovaquone and proguanil hydrochloride is used in patients who are vomiting, parasitemia should be closely monitored and the use of an antiemetic considered. [See Dosage and Administration ( 2).] Vomiting occurred in up to 19% of pediatric patients given treatment doses of atovaquone and proguanil hydrochloride. In the controlled clinical trials, 15.3% of adults received an antiemetic when they received atovaquone/proguanil and 98.3% of these patients were successfully treated. In patients with severe or persistent diarrhea or vomiting, alternative antimalarial therapy may be required.

5.2 Relapse of Infection

In mixed P. falciparum and Plasmodium vivax infections, P. vivax parasite relapse occurred commonly when patients were treated with atovaquone and proguanil hydrochloride alone.

In the event of recrudescent P. falciparum infections after treatment with atovaquone and proguanil hydrochloride or failure of chemoprophylaxis with atovaquone and proguanil hydrochloride, patients should be treated with a different blood schizonticide.

5.3 Hepatotoxicity

Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use of atovaquone and proguanil hydrochloride.

5.4 Severe or Complicated Malaria

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 therapy.

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DRUG INTERACTIONS SECTION

Highlight: * Administration with rifampin or rifabutin is known to reduce atovaquone concentrations; concomitant use with atovaquone and proguanil hydrochloride is not recommended. ( 7.1)

• Proguanil may potentiate anticoagulant effect of warfarin and other coumarin-based anticoagulants. Caution advised when initiating or withdrawing atovaquone and proguanil hydrochloride in patients on anticoagulants; coagulation tests should be closely monitored. ( 7.2)
• Tetracycline may reduce atovaquone concentrations; parasitemia should be closely monitored. ( 7.3)

7 DRUG INTERACTIONS

7.1 Rifampin/Rifabutin

Concomitant administration of rifampin or rifabutin is known to reduce atovaquone concentrations [see Clinical Pharmacology ( 12.3)] . The concomitant administration of atovaquone and proguanil hydrochloride and rifampin or rifabutin is not recommended.

7.2 Anticoagulants

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, coagulation tests should be closely monitored.

7.3 Tetracycline

Concomitant treatment with tetracycline has been associated with a reduction in plasma concentrations of atovaquone [see Clinical Pharmacology ( 12.3)] . Parasitemia should be closely monitored in patients receiving tetracycline.

7.4 Metoclopramide

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 [see Clinical Pharmacology ( 12.3)] .

7.5 Indinavir

Concomitant administration of atovaquone and indinavir did not result in any change in the steady-state AUC and C max of indinavir but resulted in a decrease in the C trough of indinavir [see Clinical Pharmacology ( 12.3)] . Caution should be exercised when prescribing atovaquone with indinavir due to the decrease in trough concentrations of indinavir.

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Genotoxicity studies have not been performed with atovaquone in combination with proguanil. Effects of atovaquone and proguanil hydrochloride on male and female reproductive performance are unknown.

Atovaquone

A 24-month carcinogenicity study in CD rats was negative for neoplasms at doses up to 500 mg/kg/day corresponding to approximately 54 times the average steady-state plasma concentrations in humans during prophylaxis of malaria. In CD-1 mice, a 24-month study showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested (50, 100, and 200 mg/kg/day) which correlated with at least 15 times the average steady-state plasma concentrations in humans during prophylaxis of malaria.

Atovaquone was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay, the mouse lymphoma mutagenesis assay, and the cultured human lymphocyte cytogenetic assay. No evidence of genotoxicity was observed in the in vivo mouse micronucleus assay.

Atovaquone administered by oral gavage in doses of 100, 300, or 1,000 mg/kg/day to adult male rats from 73 days prior to mating until 20 days after mating and to adult female rats from 14 days prior to mating until LD20 did not impair male or female fertility or early embryonic development at doses up to 1,000 mg/kg/day corresponding to plasma exposures of approximately 7.3 times the estimated human exposure for the treatment of malaria based on AUC.

Proguanil

No evidence of a carcinogenic effect was observed in 24-month studies conducted in CD-1 mice at doses up to 16 mg/kg/day corresponding to 1.5 times the average human plasma exposure during prophylaxis of malaria based on AUC, and in Wistar Hannover rats at doses up 20 mg/kg/day corresponding to 1.1 times the average human plasma exposure during prophylaxis of malaria based on AUC.

Proguanil was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay and the mouse lymphoma mutagenesis assay. No evidence of genotoxicity was observed in the in vivo mouse micronucleus assay.

Cycloguanil, the active metabolite of proguanil, was also negative in the Ames test, but was positive in the Mouse Lymphoma assay and the mouse micronucleus assay. These positive effects with cycloguanil, a dihydrofolate reductase inhibitor, were significantly reduced or abolished with folinic acid supplementation.

Proguanil administered orally in doses of 4, 8, and 16 mg/kg/day to male rats from 29 days prior to mating until 27 days after mating and to females from 15 days prior to mating through GD7 revealed no adverse effects on adult male or female fertility or early embryonic development at doses up to 16 mg/kg/day (up to 0.04 times the average human exposure for the treatment of malaria based on AUC). Fertility studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted.

13.2 Animal Toxicology and/or Pharmacology

Fibrovascular proliferation in the right atrium, pyelonephritis, bone marrow hypocellularity, lymphoid atrophy, and gastritis/enteritis were observed in dogs treated with proguanil hydrochloride for 6 months at a dose of 12 mg/kg/day (approximately 3.9 times the recommended daily human dose for malaria prophylaxis on a mg/m 2 basis). Bile duct hyperplasia, gall bladder mucosal atrophy, and interstitial pneumonia were observed in dogs treated with proguanil hydrochloride for 6 months at a dose of 4 mg/kg/day (approximately 1.3 times the recommended daily human dose for malaria prophylaxis on a mg/m 2 basis). Mucosal hyperplasia of the cecum and renal tubular basophilia were observed in rats treated with proguanil hydrochloride for 6 months at a dose of 20 mg/kg/day (approximately 1.6 times the recommended daily human dose for malaria prophylaxis on a mg/m 2 basis). Adverse heart, lung, liver, and gall bladder effects observed in dogs and kidney effects observed in rats were not shown to be reversible.

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

Atovaquone and proguanil hydrochloride tablets, containing 250 mg atovaquone, USP and 100 mg proguanil hydrochloride, USP 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 43063-393-14 bottles of 14 tablets

NDC 43063-393-20 bottles of 24 tablets

Storage Conditions

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

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SPL UNCLASSIFIED SECTION

14 CLINICAL STUDIES

14.1 Prevention of P. falciparum Malaria

Atovaquone and proguanil hydrochloride was evaluated for prophylaxis of P. falciparum malaria in 5 clinical trials in malaria-endemic areas and in 3 active-controlled trials in non-immune travelers to malaria-endemic areas.

Three placebo-controlled trials of 10 to 12 weeks’ duration were conducted among residents of malaria-endemic areas in Kenya, Zambia, and Gabon. The mean age of subjects was 30 (range: 17 to 55), 32 (range: 16 to 64), and 10 (range: 5 to 16) years, respectively. Of a total of 669 randomized patients (including 264 pediatric patients aged 5 to 16 years), 103 were withdrawn for reasons other than falciparum malaria- or drug-related adverse events (55% of these were lost to follow-up and 45% were withdrawn for protocol violations). The results are listed in Table 6.

Table 6. Prevention of Parasitemiaain Placebo-Controlled Clinical Trials of Atovaquone and Proguanil hydrochloride for Prophylaxis ofP. falciparum Malaria in Residents of Malaria-Endemic Areas

a Free of parasitemia during the 10- to 12-week period of prophylactic therapy.

In another study, 330 Gabonese pediatric patients (weighing 13 to 40 kg and aged 4 to 14 years) who had received successful open-label radical cure treatment with artesunate, were randomized to receive either atovaquone and proguanil hydrochloride (dosage based on body weight) or placebo in a double- blind fashion for 12 weeks. Blood smears were obtained weekly and any time malaria was suspected. Nineteen of the 165 children given atovaquone and proguanil hydrochloride and 18 of 165 patients given placebo withdrew from the study for reasons other than parasitemia (primary reason was lost to follow- up). One out of 150 evaluable patients (<1%) who received atovaquone and proguanil hydrochloride developed P. falciparum parasitemia while receiving prophylaxis with atovaquone and proguanil hydrochloride compared with 31 (22%) of the 144 evaluable placebo recipients.

In a 10-week study in 175 South African subjects who moved into malaria- endemic areas and were given prophylaxis with 1 atovaquone and proguanil hydrochloride tablet daily, parasitemia developed in 1 subject who missed several doses of medication. Since no placebo control was included, the incidence of malaria in this study was not known.

Two active-controlled trials were conducted in non-immune travelers who visited a malaria-endemic area. The mean duration of travel was 18 days (range: 2 to 38 days). Of a total of 1,998 randomized patients who received atovaquone and proguanil hydrochloride or controlled drug, 24 discontinued from the study before follow-up evaluation 60 days after leaving the endemic area. Nine of these were lost to follow-up, 2 withdrew because of an adverse experience, and 13 were discontinued for other reasons. These trials were not large enough to allow for statements of comparative efficacy. In addition, the true exposure rate to P. falciparum malaria in both trials is unknown. The results are listed in Table 7.

Table 7. Prevention of Parasitemiaain Active-Controlled Clinical Trials of Atovaquone and Proguanil hydrochloride for Prophylaxis ofP. falciparum Malaria in Non-Immune Travelers

a Free of parasitemia during the period of prophylactic therapy.

A third randomized, open-label study was conducted which included 221 otherwise healthy pediatric patients (weighing ≥11 kg and aged 2 to 17 years) who were at risk of contracting malaria by traveling to an endemic area. The mean duration of travel was 15 days (range: 1 to 30 days). Prophylaxis with atovaquone and proguanil hydrochloride (n = 110, dosage based on body weight) began 1 or 2 days before entering the endemic area and lasted until 7 days after leaving the area. A control group (n = 111) received prophylaxis with chloroquine/proguanil dosed according to WHO guidelines. No cases of malaria occurred in either group of children. However, the study was not large enough to allow for statements of comparative efficacy. In addition, the true exposure rate to P. falciparum malaria in this study is unknown.

Causal Prophylaxis

In separate trials with small numbers of volunteers, atovaquone and proguanil hydrochloride were independently shown to have causal prophylactic activity directed against liver-stage parasites of P. falciparum. Six patients given a single dose of atovaquone 250 mg 24 hours prior to malaria challenge were protected from developing malaria, whereas all 4 placebo-treated patients developed malaria.

During the 4 weeks following cessation of prophylaxis in clinical trial participants who remained in malaria-endemic areas and were available for evaluation, malaria developed in 24 of 211 (11.4%) subjects who took placebo and 9 of 328 (2.7%) who took atovaquone and proguanil hydrochloride. While new infections could not be distinguished from recrudescent infections, all but 1 of the infections in patients treated with atovaquone and proguanil hydrochloride occurred more than 15 days after stopping therapy. The single case occurring on Day 8 following cessation of therapy with atovaquone and proguanil hydrochloride probably represents a failure of prophylaxis with atovaquone and proguanil hydrochloride. The possibility that delayed cases of P. falciparum malaria may occur sometime after stopping prophylaxis with atovaquone and proguanil hydrochloride cannot be ruled out. Hence, returning travelers developing febrile illnesses should be investigated for malaria.

14.2 Treatment of Acute, Uncomplicated P. falciparum Malaria Infections

In 3 Phase 2 clinical trials, atovaquone alone, proguanil hydrochloride alone, and the combination of atovaquone and proguanil hydrochloride were evaluated for the treatment of acute, uncomplicated malaria caused by P. falciparum. Among 156 evaluable patients, the parasitological cure rate (elimination of parasitemia with no recurrent parasitemia during follow-up for 28 days) was 59/89 (66%) with atovaquone alone, 1/17 (6%) with proguanil hydrochloride alone, and 50/50 (100%) with the combination of atovaquone and proguanil hydrochloride.

Atovaquone and proguanil hydrochloride was evaluated for treatment of acute, uncomplicated malaria caused by P. falciparum in 8 Phase 3 randomized, open- label, controlled clinical trials (N = 1,030 enrolled in both treatment groups). The mean age of subjects was 27 years and 16% were children 12 years and younger; 74% of subjects were male. Evaluable patients included those whose outcomes at 28 days were known. Among 471 evaluable patients treated with the equivalent of 4 atovaquone and proguanil hydrochloride tablets once daily for 3 days, 464 had a sensitive response (elimination of parasitemia with no recurrent parasitemia during follow-up for 28 days) (Table 8). Seven patients had a response of RI resistance (elimination of parasitemia but with recurrent parasitemia between 7 and 28 days after starting treatment). In these trials, the response to treatment with atovaquone and proguanil hydrochloride was similar to treatment with the comparator drug in 4 trials.

Table 8. Parasitological Response in 8 Clinical Trials of Atovaquone and Proguanil hydrochloride for Treatment ofP.falciparumMalaria

a Atovaquone and proguanil hydrochloride tablets = 1,000 mg atovaquone and 400 mg proguanil hydrochloride (or equivalent based on body weight for patients weighing ≤40 kg) once daily for 3 days.

b Elimination of parasitemia with no recurrent parasitemia during follow-up for 28 days.

c Patients hospitalized only for acute care. Follow-up conducted in outpatients.

d Study in pediatric patients aged 3 to 12 years.

When these 8 trials were pooled and 2 additional trials evaluating atovaquone and proguanil hydrochloride alone (without a comparator arm) were added to the analysis, the overall efficacy (elimination of parasitemia with no recurrent parasitemia during follow-up for 28 days) in 521 evaluable patients was 98.7%.

The efficacy of atovaquone and proguanil hydrochloride in the treatment of the erythrocytic phase of non-falciparum malaria was assessed in a small number of patients. Of the 23 patients in Thailand infected with P. vivax and treated with atovaquone/proguanil hydrochloride 1,000 mg/400 mg daily for 3 days, parasitemia cleared in 21 (91.3%) at 7 days. Parasite relapse occurred commonly when P. vivax malaria was treated with atovaquone and proguanil hydrochloride alone. Relapsing malarias including P. vivax and P. ovale require additional treatment to prevent relapse.

The efficacy of atovaquone and proguanil hydrochloride in treating acute uncomplicated P. falciparum malaria in children weighing ≥ 5 and < 11 kg was examined in an open-label, randomized trial conducted in Gabon. Patients received either atovaquone and proguanil hydrochloride (2 or 3 atovaquone and proguanil hydrochloride pediatric tablets once daily depending upon body weight) for 3 days (n = 100) or amodiaquine (10 mg/kg/day) for 3 days (n = 100). In this study, the atovaquone and proguanil hydrochloride tablets were crushed and mixed with condensed milk just prior to administration. An adequate clinical response (elimination of parasitemia with no recurrent parasitemia during follow-up for 28 days) was obtained in 95% (87/92) of the evaluable pediatric patients who received atovaquone and proguanil hydrochloride and in 53% (41/78) of those evaluable who received amodiaquine. A response of RI resistance (elimination of parasitemia but with recurrent parasitemia between 7 and 28 days after starting treatment) was noted in 3% and 40% of the patients, respectively. Two cases of RIII resistance (rising parasite count despite therapy) were reported in the patients receiving atovaquone and proguanil hydrochloride. There were 4 cases of RIII in the amodiaquine arm.

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