ATOVAQUONE AND PROGUANIL HYDROCHLORIDE

Each atovaquone and proguanil hydrochloride tablet contains 250 mg of atovaquone and 100 mg proguanil hydrochloride. The daily dose should be taken with food or a milky drink (to ensure maximum absorption) at the same time each day (see PRECAUTIONS, General).

In the event of vomiting within 1 hour of dosing a repeat dose should be taken. Should vomiting continue, alternative therapy should be considered or the patient’s parasitemia should be monitored. Atovaquone and proguanil hydrochloride tablets should preferably be swallowed whole.

The tablets may be crushed and mixed with condensed milk just prior to administration for patients who may have difficulty swallowing tablets. ). Prophylaxis should be continued daily throughout the stay and for 7 additional days after leaving the area of concern.

Dosage in Adults One atovaquone and proguanil hydrochloride tablet (adult strength = 250 mg atovaquone and 100 mg proguanil hydrochloride) daily. TREATMENT Dosage in Adults Four atovaquone and proguanil hydrochloride tablets (adult strength) as a single dose for three consecutive days.

Dosage in Children (see PRECAUTIONS, Use in Children, and CLINICAL PHARMACOLOGY, Special Populations, Pediatrics) The dosage for treatment of acute malaria in children is based upon body weight. > 40 kg: Dose as for adults; Four atovaquone and proguanil hydrochloride tablets (adult strength= 250 mg atovaquone and 100 mg proguanil hydrochloride) as a single dose for three consecutive days.

SPECIAL POPULATIONS Patients with Renal Impairment:

There are no studies in children with renal impairment. However, pharmacokinetic studies in adults indicate that no dosage adjustments are needed in patients with mild to moderate renal impairment. Page 16 of 35 Atovaquone and proguanil hydrochloride tablets should not be used for malaria prophylaxis in patients with severe renal impairment (creatinine clearance < 30 mL/min), and alternatives to atovaquone and proguanil hydrochloride tablets should be recommended for treatment of acute P.

falciparum malaria whenever possible (see CONTRAINDICATIONS, PRECAUTIONS, Renal Impairment, and CLINICAL PHARMACOLOGY, Special Populations).

Patients with Hepatic Impairment:

There are no studies in children with hepatic impairment. However, a pharmacokinetic study in adults indicates that 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 PRECAUTIONS, Hepatic Impairment, and CLINICAL PHARMACOLOGY, Special Populations).

2 Description: Atovaquone: Atovaquone is a yellow powder with a melting point of ≈ 221°C. 1 M NaOH.

Proguanil Hydrochloride:

A white crystalline powder, with a melting point of 239°C to 245°C. It is slightly soluble in water and sparingly soluble in alcohol. It is practically Page 18 of 35 insoluble in methylene chloride. Comparative Bioavailability Studies A single oral dose crossover comparative bioavailability study comparing Atovaquone and Proguanil Hydrochloride (250 mg Atovaquone /100 mg Proguanil Hydrochloride Tablets), Glenmark Pharmaceuticals Canada Inc.

) was conducted in 68 healthy Asian male subjects (from 19 to 40 years of age) under fasting conditions. Bioavailability data were measured and the results from 62 subjects are summarized in Table 4 for Atovaquone; the results from the first 40 subjects to complete the study are summarized in Table 5 for Proguanil.

00) * Atovaquone and Proguanil Hydrochloride (250 mg Atovaquone /100 mg Proguanil Hydrochloride Tablets), Glenmark Pharmaceuticals Canada Inc. , was purchased in Canada. # Expressed as the median (range) only Atovaquone: N=62 ¥ n=46 for AUC0-72 Atovaquone: N=62 Note: Due to long half-life of atovaquone, AUC∞ and T1/2 are not reported due to inability to accurately estimate the terminal elimination phase.

84) * Atovaquone […]