Atovaquone and Proguanil Hydrochloride (Page 5 of 6)

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 III randomized, open-label, controlled clinical trials (N = 1,030 enrolled in both treatment goups). 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 outcome 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 of P.falciparum Malaria

Study Site

Atovaquone and Proguanil hydrochloride a

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

b

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.

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 evaulating 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 or 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.

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 68001-245-00 bottles of 100

NDC 68001-245-15 Carton containing two blister cards (NDC 68001-245-14) each containing 12 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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