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Malarone (Atovaquone / Proguanil Hydrochloride) - Description and Clinical Pharmacology

 
 



DESCRIPTION

MALARONE (atovaquone and proguanil hydrochloride) Tablets (adult strength) and MALARONE (atovaquone and proguanil hydrochloride) Pediatric Tablets, for oral administration, contain 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 is 1-(4-chlorophenyl)-5-isopropyl-biguanide hydrochloride. Proguanil hydrochloride 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:

Each MALARONE Tablet (adult strength) contains 250 mg of atovaquone and 100 mg of proguanil hydrochloride and each MALARONE Pediatric Tablet contains 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride. The inactive ingredients in both tablets are low‑substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, poloxamer 188, povidone K30, and sodium starch glycolate. The tablet coating contains hypromellose, polyethylene glycol 400, polyethylene glycol 8000, red iron oxide, and titanium dioxide.

CLINICAL PHARMACOLOGY

Mechanism of Action

The constituents of MALARONE, 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 malaria parasite disrupts deoxythymidylate synthesis.

Pharmacodynamics

No trials of the pharmacodynamics of MALARONE have been conducted.

Pharmacokinetics

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

Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC 2 to 3 times and Cmax 5 times over fasting. The absolute bioavailability of the tablet formulation of atovaquone when taken with food is 23%. MALARONE Tablets should be taken with food or a milky drink.

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 >15 years of age with body weights from 31 to 110 kg ranged from 1,617 to 2,502 L. In pediatric patients ≤15 years of age 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.

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 CYP2C19) and 4-chlorophenylbiguanide. The main routes of elimination are hepatic biotransformation and renal excretion.

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.

A population pharmacokinetic analysis in adult and pediatric patients showed that the apparent clearance (CL/F) of both atovaquone and proguanil are related to the 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

Body Weight

Atovaquone

Proguanil

N

CL/F (L/hr)

Mean ± SDa (range)

N

CL/F (L/hr)

Mean ± SDa (range)

11-20 kg

159

1.34 ± 0.63

(0.52-4.26)

146

29.5 ± 6.5

(10.3-48.3)

21-30 kg

117

1.87 ± 0.81

(0.52-5.38)

113

40.0 ± 7.5

(15.9-62.7)

31-40 kg

95

2.76 ± 2.07

(0.97-12.5)

91

49.5 ± 8.30

(25.8-71.5)

>40 kg

368

6.61 ± 3.92

(1.32-20.3)

282

67.9 ± 19.9

(14.0-145)

  •   a SD = standard deviation.

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

Pediatrics: 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.

Geriatrics: In a single‑dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 elderly subjects (age 65 to 79 years) to 13 younger subjects (age 30 to 45 years). In the elderly subjects, the extent of systemic exposure (AUC) of cycloguanil was increased (point estimate = 2.36, 90% CI = 1.70, 3.28). Tmax 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).

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 MALARONE 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 Cmax 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].

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) to 13 subjects with normal hepatic function. In subjects with mild or moderate hepatic impairment as compared to 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 = 1.00 to 1.63). Proguanil AUC, Cmax, and its elimination half-life increased in subjects with mild hepatic impairment when compared to healthy subjects (Table 5). Also, the proguanil AUC and its elimination half-life increased in subjects with moderate hepatic impairment when compared to healthy subjects. Consistent with the increase in proguanil AUC, there were marked decreases in the systemic exposure of cycloguanil (Cmax and AUC) and an increase in its elimination half‑life in subjects with mild hepatic impairment when compared to 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 MALARONE 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 to Healthy Volunteers

Parameter

Comparison

Proguanil

Cycloguanil

AUC(0-inf) a

mild:healthy

1.96 (1.51, 2.54)

0.32 (0.22, 0.45)

Cmax a

mild:healthy

1.41 (1.16, 1.71)

0.35 (0.24, 0.50)

t1/2 b

mild:healthy

1.21 (0.92, 1.60)

0.86 (0.49, 1.48)

AUC(0-inf) a

moderate:healthy

1.64 (1.14, 2.34)

ND

Cmax a

moderate:healthy

0.97 (0.69, 1.36)

ND

t1/2 b

moderate:healthy

1.46 (1.05, 2.05)

ND

ND = not determined due to lack of quantifiable data.

  •   a Ratio of geometric means.
  •   b Mean difference.

Drug Interactions: 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 Cmax of indinavir but resulted in a decrease in the Ctrough of indinavir (23% decrease [90% CI = 8%, 35%]).

Microbiology

Activity In Vitro and In Vivo: Atovaquone and cycloguanil (an active metabolite of proguanil) are active against the erythrocytic and exoerythrocytic stages of Plasmodium spp. Enhanced efficacy of the combination compared to 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)].

Drug 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.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Genotoxicity studies have not been performed with atovaquone in combination with proguanil. Effects of MALARONE 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 did not impair fertility in male and female rats at doses up to 1,000 mg/kg/day corresponding to plasma exposures of approximately 7.3 times the estimated human exposure during 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.

A fertility study in Sprague-Dawley rats revealed no adverse effects at doses up to 16 mg/kg/day of proguanil hydrochloride (up to 0.04-times the average human exposure during 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.

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/m2 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/m2 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/m2 basis). Adverse heart, lung, liver, and gall bladder effects observed in dogs and kidney effects observed in rats were not shown to be reversible.

CLINICAL STUDIES

Prevention of P. falciparum Malaria

MALARONE 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 17‑55), 32 (range 16‑64), and 10 (range 5‑16) years, respectively. Of a total of 669 randomized patients (including 264 pediatric patients 5 to 16 years of age), 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 Parasitemiaa in Placebo Controlled Clinical Trials of MALARONE for Prophylaxis of P. falciparum Malaria in Residents of Malaria Endemic Areas

MALARONE

Placebo

Total number of patients randomized

326

343

Failed to complete study

57

46

Developed parasitemia (P. falciparum)

2

92

  •   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 MALARONE (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 MALARONE 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 MALARONE developed P. falciparum parasitemia while receiving prophylaxis with MALARONE 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 MALARONE 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 MALARONE 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 Parasitemiaa in Active-Controlled Clinical Trials of MALARONE for Prophylaxis of P. falciparum Malaria in Non-Immune Travelers

MALARONE

Mefloquine

Chloroquine plus Proguanil

Total number of randomized patients who received study drug

1,004

483

511

Failed to complete study

14

6

4

Developed parasitemia (P. falciparum)

0

0

3

  •   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 2 to 17 years of age) 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 MALARONE (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 MALARONE. While new infections could not be distinguished from recrudescent infections, all but 1 of the infections in patients treated with MALARONE occurred more than 15 days after stopping therapy. The single case occurring on day 8 following cessation of therapy with MALARONE probably represents a failure of prophylaxis with MALARONE.

The possibility that delayed cases of P. falciparum malaria may occur some time after stopping prophylaxis with MALARONE cannot be ruled out. Hence, returning travelers developing febrile illnesses should be investigated for malaria.

Treatment of Acute, Uncomplicated P. falciparum Malaria Infections

In 3 phase II 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.

MALARONE was evaluated for treatment of acute, uncomplicated malaria caused by P. falciparum in 8 phase III 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 of age; 74% of subjects were male. Evaluable patients included those whose outcome at 28 days was known. Among 471 evaluable patients treated with the equivalent of 4 MALARONE 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 MALARONE was similar to treatment with the comparator drug in 4 trials.

Table 8. Parasitological Response in 8 Clinical Trials of MALARONE for Treatment of P. falciparum Malaria

Study Site

MALARONEa

Comparator

Evaluable Patients

(n)

% Sensitive

Responseb

Drug(s)

Evaluable Patients

(n)

% Sensitive Responseb

Brazil

74

98.6%

Quinine and tetracycline

76

100.0%

Thailand

79

100.0%

Mefloquine

79

86.1%

Francec

21

100.0%

Halofantrine

18

100.0%

Kenyac,d

81

93.8%

Halofantrine

83

90.4%

Zambia

80

100.0%

Pyrimethamine/

sulfadoxine (P/S)

80

98.8%

Gabonc

63

98.4%

Amodiaquine

63

81.0%

Philippines

54

100.0%

Chloroquine (Cq)

Cq and P/S

23

32

30.4%

87.5%

Peru

19

100.0%

Chloroquine

P/S

13

7

7.7%

100.0%

  •   a MALARONE = 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 3 to 12 years of age.

When these 8 trials were pooled and 2 additional trials evaluating MALARONE 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 MALARONE in the treatment of the erythrocytic phase of nonfalciparum 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 MALARONE alone. Relapsing malarias including P. vivax and P. ovale require additional treatment to prevent relapse.

The efficacy of MALARONE 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 MALARONE (2 or 3 MALARONE 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 MALARONE 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 MALARONE 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 MALARONE. There were 4 cases of RIII in the amodiaquine arm.

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