Atovaquone and Proguanil Hydrochloride (Page 3 of 6)

8.2 Lactation

Risk Summary

There are no data on the presence of atovaquone in human milk; however, proguanil is present in human milk. Atovaquone is present in rat milk (see Data). When a drug is present in animal milk, it is likely the drug will be present in human milk. There are no data on the effect of atovaquone and proguanil on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for atovaquone and proguanil hydrochloride and any potential adverse effect on the breastfed child from atovaquone and proguanil hydrochloride or from the underlying maternal condition.

Data

In a rat study with doses of 10 and 250 mg/kg, given orally by gavage on postpartum Day 11, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma at both doses. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.

8.4 Pediatric Use

Prophylaxis of Malaria:

Safety and effectiveness have not been established in pediatric patients who weigh less than 11 kg. The efficacy and safety of atovaquone and proguanil hydrochloride have been established for the prophylaxis of malaria in controlled trials involving weighing pediatric patients 11 kg or more [see Clinical Studies (14.1)].

Treatment of Malaria:

Safety and effectiveness have not been established in pediatric patients who weigh less than 5 kg. The efficacy and safety of atovaquone and proguanil hydrochloride for the treatment of malaria have been established in controlled trials involving pediatric patients weighing 5 kg or more [see Clinical Studies ( 14.2)].

8.5 Geriatric Use

Clinical trials of atovaquone and proguanil hydrochloride did not include sufficient numbers of subjects aged 65 years and older 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, and the greater frequency of concomitant disease or other drug therapy. [See Clinical Pharmacology (12.3).]

8.6 Renal Impairment

Do not use atovaquone and proguanil hydrochloride for malaria prophylaxis in patients with severe renal impairment (creatinine clearance <30 mL/min). Use with caution for the treatment of malaria in patients with severe renal impairment, only if the benefits of the 3-day treatment regimen outweigh the potential risks associated with increased drug exposure. No dosage adjustments are needed in patients with mild (creatinine clearance 50 to 80 mL/min) or moderate (creatinine clearance 30 to 50 mL/min) renal impairment. [See Clinical Pharmacology (12.3).]

8.7 Hepatic Impairment

No dosage adjustments are needed in patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3)]. No trials have been conducted in patients with severe hepatic impairment

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

11 DESCRIPTION

Atovaquone and proguanil hydrochloride tablets (adult strength) and Atovaquone and proguanil hydrochloride pediatric tablets, for oral administration, contain a fixed-dose combination of the antimalarial agents atovaquone USP and proguanil hydrochloride USP.

The chemical name of atovaquone USP is trans -2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Atovaquone USP is a yellow crystalline solid that is freely soluble in N-methyl-2-pyrrolidone and in tetrahydrofuran; soluble in chloroform; sparingly soluble in acetone and dimethyl sulfoxide; slightly soluble in octanol, ethyl acetate, polyethylene glycol 200; very slightly soluble in 0.1N sodium hydroxide; insoluble in water. It has a molecular weight of 366.84 and the molecular formula C22 H19 ClO3 . The compound has the following structural formula:

Atovaquone Chemical Structure
(click image for full-size original)

The chemical name of proguanil hydrochloride USP is 1-(4-chlorophenyl)-5-isopropyl-biguanide hydrochloride. Proguanil hydrochloride USP is a white crystalline powder slightly soluble in water, sparingly soluble in alcohol, practically insoluble in methylene chloride. It has a molecular weight of 290.22 g/mol and the molecular formula C11 H16 ClN5 •HCl. The compound has the following structural formula:

Proguanil HCl Chemical Structure
(click image for full-size original)

Each atovaquone and proguanil hydrochloride tablet (adult strength) contains 250 mg of atovaquone USP and 100 mg of proguanil hydrochloride USP and each atovaquone and proguanil hydrochloride pediatric tablets contains 62.5 mg of atovaquone USP and 25 mg of proguanil hydrochloride USP. The inactive ingredients in the tablet are colloidal silicon dioxide, ferric oxide red, hypromellose 2910, low substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, poloxamer 188, polyethylene glycol 400, polyethylene glycol 8000, povidone K30, sodium starch glycolate and titanium dioxide.

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 extend 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%.

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 of age 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 14 C-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 [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 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

Atovaquone

Proguanil

Body Weight

N

CL/F (L/hr) Mean ± SDa (range)

n

CL/F (L/hr) Mean ± SDa (range)

11 to 20 kg

159

1.34 ± 0.63 (0.52 to 4.26)

146

29.5 ± 6.5 (10.3 to 48.3)

21 to 30 kg

117

1.87 ± 0.81 (0.52 to 5.38)

113

40.0 ± 7.5 (15.9 to 62.7)

31 to 40 kg

95

2.76 ± 2.07 (0.97 to 12.5)

91

49.5 ± 8.30 (25.8 to 71.5)

>40 kg

368

6.61 ± 3.92 (1.32 to 20.3)

282

67.9 ± 19.9 (14.0 to 145)

a SD = standard deviation.

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

Specific Populations

Pediatrics 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.

Geriatrics Patients: In a single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 elderly subjects (age 65 to 79 years) with those of 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).

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 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 (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, 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 with 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 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 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 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.

Tetracyline: 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%]).

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