Atovaquone and proguanil hydrochloridepediatric tablet, film coated

Description

Atovaquone and Proguanil Hydrochloride Pediatric Tablets are 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 C 22H 19ClO 3. The compound has the following structural formula:

atovaquone chemical structure

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 C 11H 16ClN 5HCl. The compound has the following structural formula:

proguanil hydrochloride chemical structure

Atovaquone and Proguanil Hydrochloride Pediatric Tablets are for oral administration. Each Atovaquone and Proguanil Hydrochloride Pediatric Tablet contains 62.5mg of atovaquone and 25mg of proguanil hydrochloride. The inactive ingredients are low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, poloxamer 188, povidone K30, and sodium starch glycolate. The tablet coating contains hypromellose, polyethylene glycol400, polyethylene glycol8000, red iron oxide, and titanium dioxide.

Clinical pharmacology

Microbiology

Mechanism of action

Atovaquone and proguanil hydrochloride interfere with 2different 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.

Activity in vitro and in vivo

Atovaquone and cycloguanil (an active metabolite of proguanil) are active against the erythrocytic and exoerythrocytic stages of Plasmodiumspp. Enhanced efficacy of the combination compared to either atovaquone or proguanil hydrochloride alone was demonstrated in clinical studies in both immune and non-immune patients (see CLINICAL STUDIES).

Drug resistance

Strains of P. falciparumwith 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.

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 3times and C max5times over fasting. The absolute bioavailability of the tablet formulation of atovaquone when taken with food is 23%. Atovaquone and proguanil hydrochloride tablets should be taken with food or a milky drink.

Proguanil hydrochloride is extensively absorbed regardless of food intake.

Distribution

Atovaquone is highly protein bound (>99%) over the concentration range of 1 to 90mcg/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 8.8L/kg.

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

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 21days. 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 3days in adult patients.

The elimination half-life of proguanil is 12 to 21hours 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 11kg are shown in Table 1.

Table 1. Apparent Clearance for Atovaquone and Proguanil in Patients as a Function of Body Weight

Body Weight

Atovaquone

Proguanil

N

CL/F (L/hr)

MeanSD a(range)

N

CL/F (L/hr)

MeanSD a(range)

11-20 kg

159

1.340.63

(0.52-4.26)

146

29.56.5

(10.3-48.3)

21-30 kg

117

1.870.81

(0.52-5.38)

113

40.07.5

(15.9-62.7)

31-40 kg

95

2.762.07

(0.97-12.5)

91

49.58.30

(25.8-71.5)

>40 kg

368

6.613.92

(1.32-20.3)

282

67.919.9

(14.0-145)

aSD=standard deviation.

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

Special populations

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 2days) than in adult patients (2 to 3days). In clinical trials, plasma trough levels of atovaquone and proguanil in pediatric patients weighing 5 to 40kg 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 13elderly subjects (age 65 to 79years) to 13younger subjects (age 30 to 45years). In the elderly subjects, the extent of systemic exposure (AUC) of cycloguanil was increased (point estimate=2.36, CI=1.70, 3.28). T maxwas longer in elderly subjects (median 8hours) compared with younger subjects (median 4hours) and average elimination half-life was longer in elderly subjects (mean 14.9hours) compared with younger subjects (mean 8.3hours).

Hepatic impairment

In a single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13subjects with hepatic impairment (9mild, 4moderate, 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, C max, and its t 1/2increased in subjects with mild hepatic impairment when compared to healthy subjects (Table 2). Also, the proguanil AUC and its t 1/2increased 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 (C maxand AUC) and an increase in its elimination half-life in subjects with mild hepatic impairment when compared to healthy volunteers (Table 2). There were few measurable cycloguanil concentrations in subjects with moderate hepatic impairment (see DOSAGE AND ADMINISTRATION). The pharmacokinetics of atovaquone, proguanil, and cycloguanil after administration of atovaquone and proguanil have not been studied in patients with severe hepatic impairment.

Table 2. 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)

C max a

mild:healthy

1.41 (1.16, 1.71)

0.35 (0.24, 0.50)

t 1/2 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

C max a

moderate:healthy

0.97 (0.69, 1.36)

ND

t 1/2 b

moderate:healthy

1.46 (1.05, 2.05)

ND

ND=not determined due to lack of quantifiable data.

aRatio of geometric means.

bMean difference.

Renal impairment

In patients with mild renal impairment (creatinine clearance 50 to 80mL/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 >80mL/min). In patients with moderate renal impairment (creatinine clearance 30 to 50mL/min), mean oral clearance for proguanil was reduced by approximately 35% compared with patients with normal renal function (creatinine clearance >80mL/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 2months) in individuals with moderate renal failure. In patients with severe renal impairment (creatinine clearance <30mL/min), atovaquone C maxand 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).

Drug interactions

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

Concomitant treatment with tetracyclinehas been associated with approximately a 40% reduction in plasma concentrations of atovaquone.

Concomitant treatment with metoclopramidehas also been associated with decreased bioavailability of atovaquone.

Concomitant administration of rifampinor rifabutinis known to reduce atovaquone levels by approximately 50% and 34%, respectively (see PRECAUTIONS: Drug Interactions). The mechanisms of these interactions are unknown.

Concomitant administration of atovaquone (750mg BID with food for 14days) and indinavir (800mg TID without food for 14days) did not result in any change in the steady-state AUC and C maxof indinavir but resulted in a decrease in the C troughof indinavir (23% decrease [90% CI 8%, 35%]). Caution should be exercised when prescribing atovaquone with indinavir due to the decrease in trough levels of indinavir.

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 (see PRECAUTIONS: Drug Interactions). Proguanil is metabolized primarily by CYP2C19. Potential pharmacokinetic interactions with other substrates or inhibitors of this pathway are unknown.

Indications and usage

Prevention of malaria

Atovaquone and proguanil hydrochloride tablets are indicated for the prophylaxis of P.falciparummalaria, 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.falciparummalaria. 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.

Contraindications

Atovaquone and proguanil hydrochloride is contraindicated in individuals with known hypersensitivity to atovaquone or proguanil hydrochloride or any component of the formulation. Rare cases of anaphylaxis following treatment with atovaquone/proguanil have been reported.

Atovaquone and proguanil hydrochloride is contraindicated for prophylaxis of P. falciparummalaria in patients with severe renal impairment (creatinine clearance <30mL/min) (see CLINICAL PHARMACOLOGY: Special Populations: Renal Impairment).

Precautions

General

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.

Elevated liver function tests and rare cases of hepatitis have been reported with prophylactic use of atovaquone and proguanil hydrochloride. A single case of hepatic failure requiring liver transplantation has also been reported with prophylactic use.

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

Parasite relapse occurred commonly when P.vivaxmalaria was treated with atovaquone and proguanil hydrochloride alone.

In the event of recrudescent P.falciparuminfections 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.

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 1hour 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 repellents, 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).

Drug interactions

Concomitant treatment with tetracyclinehas 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, metoclopramidemay reduce the bioavailability of atovaquone and should be used only if other antiemetics are not available.

Concomitant administration of rifampinor rifabutinis 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.

Carcinogenesis, mutagenesis, impairment of fertility

Atovaquone

Carcinogenicity studies in rats were negative; 24-month studies in mice showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested which ranged from approximately 5 to 8times the average steady-state plasma concentrations in humans during prophylaxis of malaria. Atovaquone was negative with or without metabolic activation in the Ames Salmonellamutagenicity assay, the Mouse Lymphoma mutagenesis assay, and the Cultured Human Lymphocyte cytogenetic assay. No evidence of genotoxicity was observed in the invivo Mouse Micronucleus assay.

Proguanil

No evidence of a carcinogenic effect was observed in 24-month studies conducted in CD-1 mice (doses up to 1.5times the average systemic human exposure based on AUC) and in Wistar Hannover rats (doses up to 1.1times the average systemic human exposure).

Proguanil was negative with or without metabolic activation in the Ames Salmonellamutagenicity assay and the Mouse Lymphoma mutagenesis assay. No evidence of genotoxicity was observed in the invivo 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 16mg/kg/day of proguanil hydrochloride (up to 0.2-times the average human exposure based on AUC comparisons.) Fertility studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted.

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.

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 6.5times 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 1.3times 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 0.10times, 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 0.82times, 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.

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 woman.

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 5kg or more (see CLINICAL STUDIES). Safety and effectiveness have not been established in pediatric patients who weigh less than 5kg.

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 11kg or more (see CLINICAL STUDIES). Safety and effectiveness have not been established in pediatric patients who weigh less than 11kg.

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.

Adverse reactions

Because atovaquone and proguanil hydrochloride tablets contain atovaquone and proguanil hydrochloride, the type and severity of adverse reactions associated with each of the compounds may be expected. The higher treatment doses of atovaquone and proguanil hydrochloride were less well tolerated than the lower prophylactic doses.

Among adults who received atovaquone and proguanil hydrochloride for treatment of malaria, attributable adverse experiences that occurred in 5% of patients were abdominal pain (17%), nausea (12%), vomiting (12%), headache (10%), diarrhea (8%), asthenia (8%), anorexia (5%), and dizziness (5%). Treatment was discontinued prematurely due to an adverse experience in 4 of 436adults treated with atovaquone and proguanil hydrochloride.

Among pediatric patients (weighing 11 to 40kg) who received atovaquone and proguanil hydrochloride for the treatment of malaria, attributable adverse experiences that occurred in 5% of patients were vomiting (10%) and pruritus (6%). Vomiting occurred in 43 of 319 (13%) pediatric patients who did not have symptomatic malaria but were given treatment doses of atovaquone and proguanil hydrochloride for 3 days in a clinical trial. The design of this clinical trial required that any patient who vomited be withdrawn from the trial. Among pediatric patients with symptomatic malaria treated with atovaquone and proguanil hydrochloride, treatment was discontinued prematurely due to an adverse experience in 1 of 116 (0.9%).

In a study of 100pediatric patients (5 to <11kg body weight) who received atovaquone and proguanil hydrochloride for the treatment of uncomplicated P. falciparummalaria, only diarrhea (6%) occurred in 5% of patients as an adverse experience attributable to atovaquone and proguanil hydrochloride. In 3patients (3%), treatment was discontinued prematurely due to an adverse experience.

Abnormalities in laboratory tests reported in clinical trials were limited to elevations of transaminases in malaria patients being treated with atovaquone and proguanil hydrochloride. The frequency of these abnormalities varied substantially across studies of treatment and were not observed in the randomized portions of the prophylaxis trials.

In one phase III trial of malaria treatment in Thai adults, early elevations of ALT and AST were observed to occur more frequently in patients treated with atovaquone and proguanil hydrochloride compared to patients treated with an active control drug. Rates for patients who had normal baseline levels of these clinical laboratory parameters were: Day 7: ALT 26.7% vs. 15.6%; AST 16.9% vs. 8.6%. By day14 of this 28-day study, the frequency of transaminase elevations equalized across the 2groups.

In this and other studies in which transaminase elevations occurred, they were noted to persist for up to 4weeks following treatment with atovaquone and proguanil hydrochloride for malaria. None were associated with untoward clinical events.

Among subjects who received atovaquone and proguanil hydrochloride for prophylaxis of malaria in placebo-controlled trials, adverse experiences occurred in similar proportions of subjects receiving atovaquone and proguanil hydrochloride or placebo (Table 3). The most commonly reported adverse experiences possibly attributable to atovaquone and proguanil hydrochloride or placebo were headache and abdominal pain. Prophylaxis with atovaquone and proguanil hydrochloride was discontinued prematurely due to a treatment-related adverse experience in 3 of 381adults and 0 of 125pediatric patients.

Table 3. Adverse Experiences in Placebo-Controlled Clinical Trials of Atovaquone and Proguanil Hydrochloride for Prophylaxis of Malaria

Adverse Experience

Percent of Subjects With Adverse Experiences

(Percent of Subjects With Adverse Experiences Attributable to Therapy)

Adults

Children and Adolescents

Placebo

n=206

Atovaquone and Proguanil HCl a

n=206

Atovaquone and Proguanil HCl b

n=381

Placebo

n=140

Atovaquone and Proguanil HCl

n=125

Headache

27

(7)

22

(3)

17

(5)

21

(14)

19

(14)

Fever

13

(1)

5

(0)

3

(0)

11

(<1)

6

(0)

Myalgia

11

(0)

12

(0)

7

(0)

(0)

(0)

Abdominal pain

10

(5)

9

(4)

6

(3)

29

(29)

33

(31)

Cough

8

(<1)

6

(<1)

4

(1)

9

(0)

9

(0)

Diarrhea

8

(3)

6

(2)

4

(1)

3

(1)

2

(0)

Upper respiratory infection

7

(0)

8

(0)

5

(0)

(0)

<1

(0)

Dyspepsia

5

(4)

3

(2)

2

(1)

(0)

(0)

Back pain

4

(0)

8

(0)

4

(0)

(0)

(0)

Gastritis

3

(2)

3

(3)

2

(2)

(0)

(0)

Vomiting

2

(<1)

1

(<1)

<1

(<1)

6

(6)

7

(7)

Flu syndrome

1

(0)

2

(0)

4

(0)

6

(0)

9

(0)

Any adverse experience

65

(32)

54

(17)

49

(17)

62

(41)

60

(42)

aSubjects receiving the recommended dose of atovaquone and proguanil hydrochloride in placebo-controlled trials.

bSubjects receiving the recommended dose of atovaquone and proguanil hydrochloride in any trial.

In an additional placebo-controlled study of malaria prophylaxis with atovaquone and proguanil hydrochloride involving 330pediatric patients in a malaria-endemic area (see CLINICAL STUDIES), the safety profile of atovaquone and proguanil hydrochloride was consistent with that described above. The most common treatment-emergent adverse events with atovaquone and proguanil hydrochloride were abdominal pain (13%), headache (13%), and cough (10%). Abdominal pain (13% vs. 8%) and vomiting (5% vs. 3%) were reported more often with atovaquone and proguanil hydrochloride than with placebo, while fever (5% vs. 12%) and diarrhea (1% vs. 5%) were more common with placebo. No patient withdrew from the study due to an adverse experience with atovaquone and proguanil hydrochloride. No routine laboratory data were obtained during this study.

Among subjects who received atovaquone and proguanil hydrochloride for prophylaxis of malaria in clinical trials with an active comparator, adverse experiences occurred in a similar or lower proportion of subjects receiving atovaquone and proguanil hydrochloride than an active comparator (Table 4). The mean durations of dosing and the periods for which the adverse experiences are summarized in Table 4, were 28days (Study 1) and 26days (Study 2) for atovaquone and proguanil hydrochloride, 53days for mefloquine, and 49days for chloroquine plus proguanil (reflecting the different recommended dosing regimens). Fewer neuropsychiatric adverse experiences occurred in subjects who received atovaquone and proguanil hydrochloride than mefloquine. Fewer gastrointestinal adverse experiences occurred in subjects receiving atovaquone and proguanil hydrochloride than chloroquine/proguanil. Compared with active comparator drugs, subjects receiving atovaquone and proguanil hydrochloride had fewer adverse experiences overall that were attributed to prophylactic therapy (Table 4). Prophylaxis with atovaquone and proguanil hydrochloride was discontinued prematurely due to a treatment-related adverse experience in 7 of 1,004travelers.

Table 4. Adverse Experiences in Active-Controlled Clinical Trials of Atovaquone and Proguanil Hydrochloride for Prophylaxis of Malaria

Percent of Subjects With Adverse Experiences a

(Percent of Subjects With Adverse Experiences Attributable to Therapy)

Study 1

Study 2

Adverse Experience

Atovaquone and Proguanil HCl

n=493

Mefloquine

n=483

Atovaquone and Proguanil HCl

n=511

Chloroquine plus Proguanil

n=511

Diarrhea

38

(8)

36

(7)

34

(5)

39

(7)

Nausea

14

(3)

20

(8)

11

(2)

18

(7)

Abdominal pain

17

(5)

16

(5)

14

(3)

22

(6)

Headache

12

(4)

17

(7)

12

(4)

14

(4)

Dreams

7

(7)

16

(14)

6

(4)

7

(3)

Insomnia

5

(3)

16

(13)

4

(2)

5

(2)

Fever

9

(<1)

11

(1)

8

(<1)

8

(<1)

Dizziness

5

(2)

14

(9)

7

(3)

8

(4)

Vomiting

8

(1)

10

(2)

8

(0)

14

(2)

Oral ulcers

9

(6)

6

(4)

5

(4)

7

(5)

Pruritus

4

(2)

5

(2)

3

(1)

2

(<1)

Visual difficulties

2

(2)

5

(3)

3

(2)

3

(2)

Depression

<1

(<1)

5

(4)

<1

(<1)

1

(<1)

Anxiety

1

(<1)

5

(4)

<1

(<1)

1

(<1)

Any adverse experience

64

(30)

69

(42)

58

(22)

66

(28)

Any neuropsychiatric event

20

(14)

37

(29)

16

(10)

20

(10)

Any GI event

49

(16)

50

(19)

43

(12)

54

(20)

aAdverse experiences that started while receiving active study drug.

In a third active-controlled study, atovaquone and proguanil hydrochloride (n=110) was compared with chloroquine/proguanil (n=111) for the prophylaxis of malaria in 221non-immune pediatric patients (see CLINICAL STUDIES). The mean duration of exposure was 23days for atovaquone and proguanil hydrochloride, 46days for chloroquine, and 43days for proguanil, reflecting the different recommended dosage regimens for these products. Fewer patients treated with atovaquone and proguanil hydrochloride reported abdominal pain (2% vs. 7%) or nausea (<1% vs. 7%) than children who received chloroquine/proguanil. Oral ulceration (2% vs. 2%), vivid dreams (2% vs. <1%), and blurred vision (0% vs. 2%) occurred in similar proportions of patients receiving either atovaquone and proguanil hydrochloride or chloroquine/proguanil, respectively. Two patients discontinued prophylaxis with chloroquine/proguanil due to adverse events, while none of those receiving atovaquone and proguanil hydrochloride discontinued due to adverse events.

Post-marketing adverse reactions

In addition to adverse events reported from clinical trials, the following events have been identified during world-wide post-approval use of atovaquone and proguanil hydrochloride. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to atovaquone and proguanil hydrochloride.

Blood and lymphatic system disorders

Neutropenia and rarely anemia. Pancytopenia in patients with severe renal impairment treated with proguanil.

Immune system disorders

Allergic reactions including angioedema, urticaria, and rare cases of anaphylaxis and vasculitis.

Nervous system disorders

Rare cases of seizures and psychotic events (such as hallucinations); however, a causal relationship has not been established.

Gastrointestinal disorders

Stomatitis.

Hepatobiliary disorders

Elevated liver function tests and rare cases of hepatitis, cholestasis; a single case of hepatic failure requiring transplant has been reported.

Skin and subcutaneous tissue disorders

Photosensitivity, rash, and rare cases of erythema multiforme and Stevens-Johnson syndrome.

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 (1,825mg/kg/day). Overdoses up to 31,500mg 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 1,500mg have been followed by complete recovery, and doses as high as 700mg twice daily have been taken for over 2weeks without serious toxicity. Adverse experiences occasionally associated with proguanil hydrochloride doses of 100 to 200mg/day, such as epigastric 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.

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 1hour after dosing, a repeat dose should be taken.

Prevention of malaria

Prophylactic treatment with atovaquone and proguanil hydrochloride should be started 1 or 2days before entering a malaria-endemic area and continued daily during the stay and for 7days after return.

Pediatric patients

The dosage for prevention of malaria in pediatric patients is based upon body weight (Table 5).

Table 5. Dosage for Prevention of Malaria in Pediatric Patients

Weight

(kg)

Atovaquone/

ProguanilHCl

Total Daily Dose

Dosage Regimen

11-20

62.5mg/25mg

1Atovaquone and Proguanil Hydrochloride Pediatric Tablet daily

21-30

125mg/50mg

2Atovaquone and Proguanil Hydrochloride Pediatric Tablets as a single dose daily

31-40

187.5mg/75mg

3Atovaquone and Proguanil Hydrochloride Pediatric Tablets as a single dose daily

>40

250mg/100mg

1Atovaquone and Proguanil Hydrochloride Tablet (adult strength) as a single dose daily

See prescribing information for Atovaquone and Proguanil Hydrochloride Tablets (adult strength).

Treatment of acute malaria

Pediatric patients

The dosage for treatment of acute malaria in pediatric patients is based upon body weight (Table 6).

Table 6. Dosage for Treatment of Acute Malaria in Pediatric Patients

Weight

(kg)

Atovaquone/

ProguanilHCl

Total Daily Dose

Dosage Regimen

5-8

125mg/50mg

2Atovaquone and Proguanil Hydrochloride Pediatric Tablets daily for 3consecutive days

9-10

187.5mg/75mg

3Atovaquone and Proguanil Hydrochloride Pediatric Tablets daily for 3consecutive days

11-20

250mg/100mg

1Atovaquone and Proguanil Hydrochloride Tablet (adult strength) daily for 3consecutive days

21-30

500mg/200mg

2Atovaquone and Proguanil Hydrochloride Tablets (adult strength) as a single dose daily for 3consecutive days

31-40

750mg/300mg

3Atovaquone and Proguanil Hydrochloride Tablets (adult strength) as a single dose daily for 3consecutive days

>40

1g/400mg

4Atovaquone and Proguanil Hydrochloride Tablets (adult strength) as a single dose daily for 3consecutive days

See prescribing information for Atovaquone and Proguanil Hydrochloride Tablets (adult strength).

Atovaquone and proguanil hydrochloride tablets may be crushed and mixed with condensed milk just prior to administration for children who may have difficulty swallowing tablets.

Patients with renal impairment

Atovaquone and proguanil hydrochloride tablets should not be used for malaria prophylaxis in patients with severe renal impairment (creatinine clearance <30mL/min). Atovaquone and proguanil hydrochloride tablets may be used with caution for the treatment of malaria in patients with severe renal impairment (creatinine clearance <30mL/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 80mL/min) and moderate (creatinine clearance 30 to 50mL/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).

How supplied

Atovaquone and Proguanil Hydrochloride Pediatric Tablets, containing 62.5mg atovaquone and 25mg proguanil hydrochloride, are pink, film-coated, round, biconvex tablets engraved with GX CG7 on one side.

NDC 68462-563-01: Bottle of 100 tablets with child-resistant closure.

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

Atovaquone and Proguanil Hydrochloride Tablets (adult strength)are supplied as:

Tablets containing 250 mg atovaquone and 100 mg proguanil hydrochloride. [See prescribing information for Atovaquone and Proguanil Hydrochloride Tablets (adult strength).]

Animal toxicology

Fibrovascular proliferation in the right atrium, pyelonephritis, bone marrow hypocellularity, lymphoid atrophy, and gastritis/enteritis were observed in dogs treated with proguanil hydrochloride for 6months at a dose of 12mg/kg/day (approximately 3.9times the recommended daily human dose for malaria prophylaxis on a mg/m 2basis). Bile duct hyperplasia, gall bladder mucosal atrophy, and interstitial pneumonia were observed in dogs treated with proguanil hydrochloride for 6months at a dose of 4mg/kg/day (approximately 1.3times the recommended daily human dose for malaria prophylaxis on a mg/m 2basis). Mucosal hyperplasia of the cecum and renal tubular basophilia were observed in rats treated with proguanil hydrochloride for 6months at a dose of 20mg/kg/day (approximately 1.6times the recommended daily human dose for malaria prophylaxis on a mg/m 2basis). 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

Treatment of acute malarial infections

In 3phase 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 156evaluable patients, the parasitological cure rate 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.falciparumin 8phase III controlled clinical trials. Among 471evaluable patients treated with the equivalent of 4Atovaquone and Proguanil Hydrochloride Tablets (adult strength) once daily for 3days, 464 had a sensitive response (elimination of parasitemia with no recurrent parasitemia during follow-up for 28days) (see Table7). Seven patients had a response of RI resistance (elimination of parasitemia but with recurrent parasitemia between 7 and 28days after starting treatment). In these trials, the response to treatment with atovaquone and proguanil hydrochloride was similar to treatment with the comparator drug in 4trials, and better than the response to treatment with the comparator drug in the other 4trials.

The overall efficacy in 521evaluable patients was 98.7% (Table 7).

Table 7. Parasitological Response in Clinical Trials of Atovaquone and Proguanil Hydrochloride for Treatment of P.falciparum Malaria

Study Site

Atovaquone and

Proguanil HCl a

Comparator

Evaluable Patients

(n)

% Sensitive

Response b

Drug(s)

Evaluable Patients

(n)

% Sensitive Response b

Brazil

74

98.6%

Quinine and tetracycline

76

100.0%

Thailand

79

100.0%

Mefloquine

79

86.1%

France c

21

100.0%

Halofantrine

18

100.0%

Kenya c,d

81

93.8%

Halofantrine

83

90.4%

Zambia

80

100.0%

Pyrimethamine/

sulfadoxine (P/S)

80

98.8%

Gabon c

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%

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

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

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

dStudy in pediatric patients 3 to 12years of age.

Eighteen of 521 (3.5%) evaluable patients with acute falciparum malaria presented with a pretreatment serum creatinine greater than 2.0mg/dL (range 2.1 to 4.3mg/dL). All were successfully treated with atovaquone and proguanil hydrochloride and 17 of 18 (94.4%) had normal serum creatinine levels by day7.

Data from a phase II trial of atovaquone conducted in Zambia suggested that approximately 40% of the study population in this country were HIV-infected patients. The enrollment criteria were similar for the phase III trial of atovaquone and proguanil hydrochloride conducted in Zambia and the results are presented in Table7. Efficacy rates for atovaquone and proguanil hydrochloride in this study population were high and comparable to other populations studied.

The efficacy of atovaquone and proguanil hydrochloride in the treatment of the erythrocytic phase of nonfalciparum malaria was assessed in a small number of patients. Of the 23patients in Thailand infected with P. vivaxand treated with atovaquone/proguanil hydrochloride 1,000mg/400mg daily for 3days, parasitemia cleared in 21(91.3%) at 7days. Parasite relapse occurred commonly when P.vivaxmalaria was treated with atovaquone and proguanil hydrochloride alone. Seven patients in Gabon with malaria due to P.ovaleor P.malariaewere treated with atovaquone/proguanil hydrochloride 1,000mg/400mg daily for 3days. All 6evaluable patients (3 with P. malariae, 2 with P.ovale, and 1 with mixed P.falciparumand P.ovale) were cured at 28days. Relapsing malarias including P.vivaxand P.ovalerequire additional treatment to prevent relapse.

The efficacy of atovaquone and proguanil hydrochloride in treating acute uncomplicated P.falciparummalaria in children weighing 5 and <11kg was examined in an open-label, randomized trial conducted in Gabon. Patients received either 2 or 3 Atovaquone and Proguanil Hydrochloride Pediatric Tablets once daily depending upon body weight for 3days (n=100), or amodiaquine (10mg/kg/day) for 3days (n=100). In this study, the Atovaquone and Proguanil Hydrochloride Pediatric Tablets were crushed and mixed with condensed milk just prior to administration. In the per-protocol population, adequate clinical response was obtained in 95% (87/92) of the pediatric patients who received Atovaquone and Proguanil Hydrochloride Pediatric Tablets and in 53% (41/78) of those who received amodiaquine. A response of RI resistance (elimination of parasitemia but with recurrent parasitemia between 7 and 28days 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 Pediatric Tablets. There were 4 cases of RIII in the amodiaquine arm.

Prevention of malaria

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

Three placebo-controlled studies of 10 to 12 weeks duration were conducted among residents of malaria-endemic areas in Kenya, Zambia, and Gabon. Of a total of 669randomized patients (including 264pediatric patients 5 to 16years of age), 103 were withdrawn for reasons other than falciparum malaria or drug-related adverse events. (Fifty-five percent of these were lost to follow-up and 45% were withdrawn for protocol violations.) The results are listed in Table8.

Table 8. Prevention of Parasitemia in Placebo-Controlled Clinical Trials of Atovaquone and Proguanil Hydrochloride for Prophylaxis of P.falciparum Malaria in Residents of Malaria-Endemic Areas

Atovaquone and Proguanil HCl

Placebo

Total number of patients randomized

326

341

Failed to complete study

57

44

Developed parasitemia ( P.falciparum)

2

92

In another study, 330Gabonese pediatric patients (weighing 13 to 40kg, and aged 4 to 14years) 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 12weeks. Blood smears were obtained weekly and any time malaria was suspected. Nineteen of the 165children 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). In the per-protocol population, 1 out of 150 patients (<1%) who received atovaquone and proguanil hydrochloride developed P.falciparumparasitemia while receiving prophylaxis with atovaquone and proguanil hydrochloride compared with 31 (22%) of the 144placebo recipients.

In a 10-week study in 175South African subjects who moved into malaria-endemic areas and were given prophylaxis with 1Atovaquone and Proguanil Hydrochloride Tablet (adult strength) daily, parasitemia developed in 1subject 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 studies were conducted in non-immune travelers who visited a malaria-endemic area. The mean duration of travel was 18days (range 2 to 38days). 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 60days 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 studies were not large enough to allow for statements of comparative efficacy. In addition, the true exposure rate to P. falciparummalaria in both studies is unknown. The results are listed in Table 9.

Table 9. Prevention of Parasitemia in Active-Controlled Clinical Trials of Atovaquone and Proguanil Hydrochloride for Prophylaxis of P. falciparum Malaria in Non-Immune Travelers

Atovaquone and Proguanil HCl

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)

3

A third randomized, open-label study was conducted which included 221 otherwise healthy pediatric patients (weighing 11kg and 2 to 17years of age) who were at risk of contracting malaria by traveling to an endemic area. The mean duration of travel was 15days (range 1 to 30days). Prophylaxis with atovaquone and proguanil hydrochloride (n=110, dosage based on body weight) began 1 or 2days before entering the endemic area and lasted until 7days 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. falciparummalaria in this study is unknown.

In a malaria challenge study conducted in healthy US volunteers, atovaquone alone prevented malaria in 6 of 6 individuals, whereas 4 of 4placebo-treated volunteers developed malaria.

Causal prophylaxis

In separate studies 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 250mg 24hours prior to malaria challenge were protected from developing malaria, whereas all 4placebo-treated patients developed malaria.

During the 4weeks 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 15days after stopping therapy, probably representing new infections. The single case occurring on day8 following cessation of therapy probably represents a failure of prophylaxis with atovaquone and proguanil hydrochloride.

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

Manufactured by:

GlaxoSmithKline

Research Triangle Park, NC 27709

Manufactured for:

Glenmark Generics Inc., USA

Mahwah, NJ 07430

Questions? 1 (888)721-7115

www.glenmarkgenerics.com

August 2011

APH-GM:1PI

Ingredients and appearance - Product information

Atovaquone and proguanil hydrochloridepediatric tablet, film coated- Atovaquone and proguanil hydrochloride

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 68462-563
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Atovaquone ( UNII: Y883P1Z2LT)( Atovaquone - UNII: Y883P1Z2LT ) 62.5 mgin 1
Proguanil hydrochloride ( UNII: R71Y86M0WT)( Proguanil - UNII: S61K3P7B2V ) 25 mgin 1

Inactive Ingredients

Ingredient Name Code
Hydroxypropyl cellulose, low substituted ( UNII: 2165RE0K14)
Magnesium stearate ( UNII: 70097M6I30)
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Poloxamer 188 ( UNII: LQA7B6G8JG)
Povidone k30 ( UNII: U725QWY32X)
Sodium starch glycolate type a potato ( UNII: 5856J3G2A2)
Hypromelloses ( UNII: 3NXW29V3WO)
Polyethylene glycol 400 ( UNII: B697894SGQ)
Polyethylene glycol 8000 ( UNII: Q662QK8M3B)
Ferric oxide red ( UNII: 1K09F3G675)
Titanium dioxide ( UNII: 15FIX9V2JP)

Product Characteristics

Color PINK Size 7 mm
Shape ROUND Score 1
Imprint Code GX;CG7

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
NDA authorized generic NDA021078 USA

Labeler - Glenmark Generics Inc( 130597813)

Principal display panel

NDC 68462-563-01

ATOVAQUONE AND PROGUANIL HYDROCHLORIDE PEDIATRIC TABLETS

Glenmark

62.5 mg / 25 mg

Rx only

100 Tablets

Each pediatric tablet contains 62.5 mg atovaquone and 25 mg proguanil hydrochloride.

See accompanying prescribing information for Dosage and Administration.

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

Dispense in a tight, light-resistant container.

Do not use if printed safety seal under cap is broken or missing.

Manufactured by:

GlaxoSmithKline

Research Triangle Park

NC 27709

Manufactured for:

Glenmark Generics Inc., USA

Mahwah, NJ 07430

Made in Canada

Questions? 1 (888)721-7115

www.glenmarkgenerics.com

A096254