malarone
Generic Name: (
atovaquone and proguanil hydrochloride)
Dosage Type: tablet, coated Organization: GlaxoSmithKline
DESCRIPTION
MALARONE (atovaquone
and proguanil hydrochloride) is 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:
MALARONE
Tablets and MALARONE Pediatric Tablets are for oral administration. Each MALARONE
Tablet 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
Microbiology
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.
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 studies in both immune and non-immune patients (see CLINICAL STUDIES).
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.
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.
Proguanil hydrochloride is extensively
absorbed regardless of food intake.
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 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)
Mean ± SD* (range)
|
N
|
CL/F (L/hr)
Mean ± SD* (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)
|
The
pharmacokinetics of atovaquone and proguanil in patients with body weight
below 11 kg 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 2 days) than in
adult patients (2 to 3 days). In clinical trials, plasma trough levels
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, 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).
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 moderatehepatic 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
t1/2 increased in subjects with mild hepatic impairment when compared
to healthy subjects (Table 2). Also, the proguanil AUC and its t1/2 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 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 MALARONE 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)*
|
mild:healthy
|
1.96 (1.51, 2.54)
|
0.32 (0.22, 0.45)
|
|
Cmax*
|
mild:healthy
|
1.41 (1.16, 1.71)
|
0.35 (0.24, 0.50)
|
|
t1/2†
|
mild:healthy
|
1.21 (0.92, 1.60)
|
0.86 (0.49, 1.48)
|
|
AUC(0-inf)*
|
moderate:healthy
|
1.64 (1.14, 2.34)
|
ND
|
|
Cmax*
|
moderate:healthy
|
0.97 (0.69, 1.36)
|
ND
|
|
t1/2†
|
moderate:healthy
|
1.46 (1.05, 2.05)
|
ND
|
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).
Drug Interactions
There are no pharmacokinetic interactions between atovaquone
and proguanil at the recommended dose.
Concomitant
treatment with tetracycline has been associated
with approximately a 40% reduction in plasma concentrations of atovaquone.
Concomitant
treatment with metoclopramide has also
been associated with decreased bioavailability of atovaquone.
Concomitant
administration of rifampin or rifabutin is known to reduce atovaquone levels
by approximately 50% and 34%, respectively (see PRECAUTIONS: Drug Interactions).
The mechanisms of these interactions are unknown.
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
MALARONE is indicated for the prophylaxis of P. falciparum malaria, including in areas where chloroquine resistance has been
reported (see CLINICAL STUDIES).
Treatment of Malaria
MALARONE is indicated for the treatment of acute, uncomplicated P. falciparum malaria. MALARONE has 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
MALARONE 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.
MALARONE is contraindicated for prophylaxis
of P. falciparum malaria in patients
with severe renal impairment (creatinine clearance <30 mL/min) (see
CLINICAL PHARMACOLOGY: Special Populations: Renal Impairment).
Warnings
PRECAUTIONS
General
MALARONE 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.
Absorption of atovaquone may be reduced
in patients with diarrhea or vomiting. If MALARONE 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 MALARONE. In the controlled
clinical trials of MALARONE, 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. vivax malaria
was treated with MALARONE alone.
In the event of recrudescent P. falciparum infections after treatment
with MALARONE or failure of chemoprophylaxis with MALARONE, patients should
be treated with a different blood schizonticide.
Information for Patients
Patients should be instructed:
- to take MALARONE tablets at the same time each day with food or a milky
drink.
- to take a repeat dose of MALARONE if vomiting occurs within 1 hour
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.
- to consult a healthcare professional regarding alternative forms of
prophylaxis if prophylaxis with MALARONE 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 tetracycline has 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
MALARONE, metoclopramide may reduce the
bioavailability of atovaquone and should be used only if other antiemetics
are not available.
Concomitant administration of rifampin or rifabutin is known to reduce atovaquone levels by approximately 50% and
34%, respectively. The concomitant administration of MALARONE and rifampin
or rifabutin is not recommended.
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 8 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.
Proguanil
No evidence of a carcinogenic effect was observed in 24-month
studies conducted in CD-1 mice (doses up to 1.5 times the average systemic
human exposure based on AUC) and in Wistar Hannover rats (doses up to 1.1 times
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 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.
Genotoxicity studies
have not been performed with atovaquone in combination with proguanil. Effects
of MALARONE 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 6.5 times 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 1.3 times 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.
The combination of
atovaquone and proguanil hydrochloride was not teratogenic in rats at plasma
concentrations up to 1.7 and 0.10 times, 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 0.82 times,
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, MALARONE may be used if the potential benefit
justifies the potential risk to the fetus. The proguanil component of MALARONE
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 MALARONE.
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 MALARONE is administered to a nursing woman.
Pediatric Use
Treatment of Malaria
The efficacy and safety of MALARONE for the treatment of
malaria have been established in controlled studies involving pediatric patients
weighing 5 kg or more (see CLINICAL STUDIES). Safety and effectiveness
have not been established in pediatric patients who weigh less than 5 kg.
Prophylaxis of Malaria
The efficacy and safety of MALARONE have been established
for the prophylaxis of malaria in controlled studies involving pediatric patients
weighing 11 kg or more (see CLINICAL STUDIES). Safety and effectiveness
have not been established in pediatric patients who weigh less than 11 kg.
Geriatric Use
Clinical studies of MALARONE 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 MALARONE contains
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 MALARONE were less well tolerated than the lower prophylactic doses.
Among
adults who received MALARONE 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 436 adults treated with MALARONE.
Among
pediatric patients (weighing 11 to 40 kg) who received MALARONE 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 MALARONE 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 MALARONE, treatment was discontinued prematurely due to an adverse experience
in 1 of 116 (0.9%).
In a study of 100 pediatric
patients (5 to <11 kg body weight) who received MALARONE for the treatment
of uncomplicated P. falciparum malaria,
only diarrhea (6%) occurred in =5% of patients as an adverse experience
attributable to MALARONE. In 3 patients (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 MALARONE. 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 MALARONE 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 day 14 of this
28-day study, the frequency of transaminase elevations equalized across the
2 groups.
In this and other studies in which transaminase
elevations occurred, they were noted to persist for up to 4 weeks following
treatment with MALARONE for malaria. None were associated with untoward clinical
events.
Among subjects who received MALARONE for prophylaxis
of malaria in placebo-controlled trials, adverse experiences occurred in similar
proportions of subjects receiving MALARONE or placebo (Table 3). The most
commonly reported adverse experiences possibly attributable to MALARONE or
placebo were headache and abdominal pain. Prophylaxis with MALARONE was discontinued
prematurely due to a treatment-related adverse experience in 3 of 381 adults
and 0 of 125 pediatric patients.
Table
3. Adverse Experiences in Placebo-Controlled Clinical Trials of MALARONE 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
|
MALARONE*
n = 206
|
MALARONE†
n = 381
|
Placebo
n = 140
|
MALARONE
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)
|
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
|
(0)
|
<1
|
(0)
|
|
Dyspepsia
|
5
|
(4)
|
3
|
(2)
|
2
|
(1)
|
0
|
(0)
|
0
|
(0)
|
|
Back pain
|
4
|
(0)
|
8
|
(0)
|
4
|
(0)
|
0
|
(0)
|
0
|
(0)
|
|
Gastritis
|
3
|
(2)
|
3
|
(3)
|
2
|
(2)
|
0
|
(0)
|
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)
|
In an additional placebo-controlled study
of malaria prophylaxis with MALARONE involving 330 pediatric patients
in a malaria-endemic area (see CLINICAL STUDIES), the safety profile of MALARONE
was consistent with that described above. The most common treatment-emergent
adverse events with MALARONE were abdominal pain (13%), headache (13%), and
cough (10%). Abdominal pain (13% vs. 8%) and vomiting (5% vs. 3%) were reported
more often with MALARONE 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 MALARONE. No routine laboratory data were
obtained during this study.
Among subjects who received
MALARONE for prophylaxis of malaria in clinical trials with an active comparator,
adverse experiences occurred in a similar or lower proportion of subjects
receiving MALARONE 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 28 days (Study 1) and 26 days (Study 2) for MALARONE,
53 days for mefloquine, and 49 days for chloroquine plus proguanil
(reflecting the different recommended dosing regimens). Fewer neuropsychiatric
adverse experiences occurred in subjects who received MALARONE than mefloquine.
Fewer gastrointestinal adverse experiences occurred in subjects receiving
MALARONE than chloroquine/proguanil. Compared with active comparator drugs,
subjects receiving MALARONE had fewer adverse experiences overall that were
attributed to prophylactic therapy (Table 4). Prophylaxis with MALARONE was
discontinued prematurely due to a treatment-related adverse experience in
7 of 1,004 travelers.
Table 4.
Adverse Experiences in Active-Controlled Clinical Trials of MALARONE for Prophylaxis
of Malaria
|
|
Percent of Subjects
With Adverse Experiences*
(Percent of Subjects
With Adverse Experiences Attributable to Therapy)
|
|
|
Study 1
|
Study 2
|
|
Adverse
Experience
|
MALARONE
n = 493
|
Mefloquine
n = 483
|
MALARONE
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)
|
In a third
active-controlled study, MALARONE (n = 110) was compared with chloroquine/proguanil
(n = 111) for the prophylaxis of malaria in 221 non-immune
pediatric patients (see CLINICAL STUDIES). The mean duration of exposure was
23 days for MALARONE, 46 days for chloroquine, and 43 days
for proguanil, reflecting the different recommended dosage regimens for these
products. Fewer patients treated with MALARONE 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 MALARONE
or chloroquine/proguanil, respectively. Two patients discontinued prophylaxis
with chloroquine/proguanil due to adverse events, while none of those receiving
MALARONE 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 MALARONE or its components, 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 MALARONE.
Blood and Lymphatic System Disorders
Anemia and neutropenia in patients treated with atovaquone.
Pancytopenia in patients with severe renal impairment treated with proguanil.
Immune System Disorders
Allergic reactions including angioedema, uticaria and rare
cases of anaphylaxis.
Metabolism and Nutrition Disorders
Elevated amylase levels and hyponatremia in patients treated
with atovaquone.
Nervous System Disorders
Rare cases of seizures and psychotic events (such as hallucinations);
however, a causal relationship has not been established.
Hepatobiliary Disorders
Very rare reports of hepatitis.
Skin and Subcutaneous Tissue Disorders
Photosensitivity, rash, and rare cases of erythema multiforme
and Steven-Johnson syndrome.
OVERDOSAGE
There is no information
on overdoses of MALARONE 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 (1,825 mg/kg/day).
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.
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 1 hour after
dosing, a repeat dose should be taken.
Prevention of Malaria
Prophylactic treatment with MALARONE should be started 1
or 2 days before entering a malaria-endemic area and continued daily
during the stay and for 7 days after return.
Adults
One MALARONE Tablet (adult strength = 250 mg
atovaquone/100 mg proguanil hydrochloride) per day.
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/
Proguanil HCl
Total
Daily Dose
|
Dosage Regimen
|
|
11-20
|
62.5 mg/25 mg
|
1 MALARONE Pediatric Tablet daily
|
|
21-30
|
125 mg/50 mg
|
2 MALARONE Pediatric Tablets as a single
dose daily
|
|
31-40
|
187.5 mg/75 mg
|
3 MALARONE Pediatric Tablets as a single
dose daily
|
|
>40
|
250 mg/100 mg
|
1 MALARONE Tablet (adult strength) as a single
dose daily
|
Treatment of Acute Malaria
Adults
Four MALARONE Tablets (adult strength; total daily dose
1 g atovaquone/400 mg proguanil hydrochloride) as a single dose
daily for 3 consecutive days.
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/
Proguanil HCl
Total
Daily Dose
|
Dosage Regimen
|
|
5-8
|
125 mg/50 mg
|
2 MALARONE Pediatric Tablets daily for 3 consecutive
days
|
|
9-10
|
187.5 mg/75 mg
|
3 MALARONE Pediatric Tablets daily for 3 consecutive
days
|
|
11-20
|
250 mg/100 mg
|
1 MALARONE Tablet (adult strength) daily
for 3 consecutive days
|
|
21-30
|
500 mg/200 mg
|
2 MALARONE Tablets (adult strength) as a
single dose daily for 3 consecutive days
|
|
31-40
|
750 mg/300 mg
|
3 MALARONE Tablets (adult strength) as a
single dose daily for 3 consecutive days
|
|
>40
|
1 g/400 mg
|
4 MALARONE Tablets (adult strength) as a
single dose daily for 3 consecutive days
|
MALARONE 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
MALARONE should not be used for malaria prophylaxis in patients
with severe renal impairment (creatinine clearance <30 mL/min). MALARONE
may be used with caution for the treatment of malaria in patients with severe
renal impairment (creatinine clearance <30 mL/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 80 mL/min) and moderate (creatinine clearance 30 to 50 mL/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
MALARONE Tablets, containing 250 mg atovaquone and
100 mg proguanil hydrochloride, are pink, film-coated, round, biconvex
tablets engraved with “GX CM3” on one side.
Bottle
of 100 tablets with child-resistant closure (NDC 0173-0675-01).
Unit
Dose Pack of 24 (NDC 0173-0675-02).
MALARONE Pediatric
Tablets, containing 62.5 mg atovaquone and 25 mg proguanil hydrochloride,
are pink, film-coated, round, biconvex tablets engraved with “GX CG7”
on one side.
Bottle of 100 tablets with child-resistant
closure (NDC 0173-0676-01).
Storeat 25°C (77°F); excursions permitted to 15° to 30°C (59°
to 86°F) (see USP Controlled Room Temperature).
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 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
Treatment of Acute Malarial 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 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 controlled
clinical trials. 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) (see Table 7). 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, and better than the response to treatment with the
comparator drug in the other 4 trials.
The overall
efficacy in 521 evaluable patients was 98.7% (Table 7).
|
|
MALARONE*
|
Comparator
|
|
Study Site
|
Evaluable Patients
(n)
|
% Sensitive
Response†
|
Drug(s)
|
Evaluable Patients
(n)
|
% Sensitive Response†
|
|
Brazil
|
74
|
98.6%
|
Quinine and tetracycline
|
76
|
100.0%
|
|
Thailand
|
79
|
100.0%
|
Mefloquine
|
79
|
86.1%
|
|
France‡
|
21
|
100.0%
|
Halofantrine
|
18
|
100.0%
|
|
Kenya‡,§
|
81
|
93.8%
|
Halofantrine
|
83
|
90.4%
|
|
Zambia
|
80
|
100.0%
|
Pyrimethamine/
sulfadoxine
(P/S)
|
80
|
98.8%
|
|
Gabon‡
|
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%
|
Eighteen
of 521 (3.5%) evaluable patients with acute falciparummalaria presented with a pretreatment serum creatinine greater than
2.0 mg/dL (range 2.1 to 4.3 mg/dL). All were successfully treated
with MALARONE and 17 of 18 (94.4%) had normal serum creatinine levels by day 7.
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 MALARONE conducted
in Zambia and the results are presented in Table 7. Efficacy rates for
MALARONE in this study population were high and comparable to other populations
studied.
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. Seven patients in Gabon with malaria due to P. ovale or P. malariae were treated with atovaquone/proguanil hydrochloride 1,000 mg/400 mg
daily for 3 days. All 6 evaluable patients (3 with P.
malariae, 2 with P. ovale,
and 1 with mixed P. falciparum and P. ovale) were cured at 28 days. 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. In the per-protocol
population, adequate clinical response was obtained in 95% (87/92) of the
pediatric patients who received MALARONE 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 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.
Prevention of Malaria
MALARONE was evaluated for prophylaxis of 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 studies of 10 to 12 weeks’ duration were conducted
among residents of malaria-endemic areas in Kenya, Zambia, and Gabon. 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. (Fifty-five percent of these were
lost to follow-up and 45% were withdrawn for protocol violations.) The results
are listed in Table 8.
|
|
MALARONE
|
Placebo
|
|
Total number of patients randomized
|
326
|
341
|
|
Failed to complete study
|
57
|
44
|
|
Developed parasitemia (P. falciparum)
|
2
|
92
|
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). In the per-protocol
population, 1 out of 150 patients (<1%) who received MALARONE developed P. falciparum parasitemia while receiving
prophylaxis with MALARONE compared with 31 (22%) of the 144 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 studies 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 studies
were not large enough to allow for statements of comparative efficacy. In
addition, the true exposure rate to P. falciparum malaria in both studies is unknown. The results are listed in
Table 9.
|
|
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 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.
In
a malaria challenge study conducted in healthy US volunteers, atovaquone alone
prevented malaria in 6 of 6 individuals, whereas 4 of 4 placebo-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 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, probably representing
new infections. 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.
GlaxoSmithKline
July
2006 RL-2291
Research Triangle Park, NC 27709
©2006,
GlaxoSmithKline. All rights reserved.
| MALARONE (atovaquone and proguanil hydrochloride) |
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| MALARONE (atovaquone and proguanil hydrochloride) |
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Revised: 07/2006GlaxoSmithKline