Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00079
 Material Information
Title: PharmaNote
Physical Description: Serial
Language: English
Creator: College of Pharmacy, University of Florida
Publisher: College of Pharmacy
Place of Publication: Gainesville, Fla.
Publication Date: November 2009
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Bibliographic ID: UF00087345
Volume ID: VID00079
Source Institution: University of Florida
Holding Location: University of Florida
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Ogechukwu Umerah, Pharm.D. Candidate

M alaria is an infectious disease transmitted
predominantly through the bite of an in-
fected female Anopheline mosquito. Of the
parasitic species that infect humans, Plasmodium
vivax, P. malariae, P. ovale, and P. falciparum, the latter
causes the most severe form of the disease and may
lead to anemia, renal failure, pulmonary edema or gas-
troenteritis.1 Malaria preferentially affects pregnant
women and children under 5 years of age. Immuno-
compromised individuals are associated with higher
parasite densities and a higher probability of more
severe and fatal malaria infections.2 Temperate cli-
mates as well as rainy seasons conducive for mosquito
growth are additional risk factors that contribute to
malaria transmission.
Malaria, a treatable and preventable disease, has
also been called a disease of poverty as it is mainly
found in the poorest regions of the world & developing
countries.3 According to the 2008 World Malaria Re-
port, there are an estimated 247 million cases and
nearly 1 million deaths worldwide.3 Although malaria
occurs in over 90 countries, the majority of cases
(91%) are found in Sub-Sahara Africa. While the
prevalence in the United States has increased, as of
2007, malaria has accounted for merely 1505 cases
and only 1 death.4An estimated $1800 million is spent
on direct costs of treatment and disease prevention as
well as indirect cost including lost time due to morbid-
ity and premature mortality.5 This heavy financial bur-

den can hinder the economic and community growth
throughout developing regions.
Management of malaria pharmacotherapy has like-
wise grown increasingly complex as resistance to tra-
ditional drug therapy has emerged resulting in an in-
crease in financial cost and difficulty in achieving a
cure. This article will review the efficacy of established
pharmacologic treatment options, as well as Coar-
tem (artemether and lumefantrine), a Novartis
manufactured agent approved by the FDA in April
2009 for the management of uncomplicated malaria.
This article will also address prevention, prophylaxis
and treatment recommendations for international


Following a bite from an infected Anopheline mos-
quito, sporozoites are released from their salivary
glands into the host's circulation. Sporozoites aggre-
gate in human hepatic tissue where they can mature
into tissue schizonts.6 Eventually, these tissue
schizonts rupture and release their content containing
merozoites that specifically target and invade erythro-
cytes.7 The parasites within the erythrocytes ulti-
mately develop into schizonts. The cycle continues as
schizonts release merozoites, merozoites attack addi-
tional erythrocytes, and parasites within erythrocytes
mature into schizonts. Finally, circulating merozoites
develop into gametocytes that are ingested from the



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Volume 25, Issue 2 1 November 2009


host by a new mosquito.6 It is important to note that
when the tissue schizonts of P. malariae and P.falcipa-
rum rupture, all forms of the parasite exit the liver.
However, the tissue parasite of P. vivax and P.ovale can
remain dormant in the liver in a stage known as hyp-
nozoites. Lingering parasites can result in relapses of
erythocytic infection that can occur months to years
after the initial attack.5


Established antimalarial treatment options are
classified based on the stage in the parasite life cycle
that they inhibit. For example, hepatic tissue schizonti-
cides target the liver stages of the parasite; treatment
options include atovaquone & proguanil (Malarone)
& primaquine. Hypnozoiticides are active against the
dormant forms of P. vivax and P. ovale and include pri-
maquine. Lastly, blood schizonticides target the asex-
ual blood stages of the parasite and include chloro-
quine (Aralen), mefloquine (Lariam), Malarone,
tetracyclines, and primaquine. Table 1 summarizes the
mechanism of action, treatment indication, dosing
regimen, common adverse events and cost of these
The inexpensive cost, ease of accessibility & the
management of malaria by a single agent, has lead to
increased resistance to the previously mentioned anti-
malarial treatment options. Resistance to chloroquine,
the drug choice for malaria since 1946, was first docu-
mented in 1957. pyrimethamine and sulfadoxine was
recommended to replace chloroquine but resistance
was reported within the same year the drug was intro-
duced.6 Similarly, resistance to mefloquine was re-
ported only five years after its introduction.6 Wide-
spread misuse of these agents has likewise facilitated
the emergence of P.falciparum resistance to nearly all
currently available antimalarials.7 As a result, the
World Health Organization opposes single agent anti-
malarial treatment despite the temptation to reduce
the cost for the patient8 Currently, the recommenda-
tion is for two or more schizonticidal agents with inde-
pendent mechanisms of actions as well as molecular
targets. This approach should result in synergistic ef-
fects of these two agents.3


Resistance has emerged to all antimalarial classes
except a novel class known as artemisinins.9 However,
decreased parasite clearance times have been shown
in areas where an artemisinin is used as monotherapy
compared to artemisinin combination therapy (ACT)
(p<0.001).10In order to delay or prevent emergence of

resistance, artemisinins are combined with one of sev-
eral longer-acting drugs including amodiaquine, meflo-
quine, sulfadoxine/pyrimethamine or lumefantrine.6
Although successfully used internationally for several
years, Coartem is the only ACT agent FDA approved
for treatment of acute, uncomplicated malaria infec-
tions in adults and children (weighing at least 5kg)
within the United States.
Coartem, an artemisinin-based, fixed combina-
tion antimalarial consists of 20 mg artemether and
120 mg lumefantrine. Combining the two medications
in one tablet prevents both single agent use and facili-
tation of subsequent resistance. These two drugs syn-
ergistically interfere with the use of hemoglobin by the
parasite.11 Additionally, these two agents are effective
in eliminating the parasite from the host but by differ-
ing mechanisms. Artemether rapidly reduces 95% of
the parasite population. However, the short half life of
artemether, renders the Coartem inappropriate for
prophylatic therapy. Lumefantrine's long half life, (t 1/2
4 days) allows it to eliminate residual, very low resis-
tance risk parasites.12 Table 2 summarizes the phar-
macokinetics, effective treatment dose, relative side
effects of Coartem. The reported cost was deter-
mined by average prices from local pharmacies. How-
ever, in order to make the medication more accessible
for developing countries, Norvatis has subsidized the
cost to around $0.9 to $1.40 for a treatment course of a
child up to 7 years old and around $ 2.4 per adult
treatment dose.13

Coartem usually is given over six days in mul-
tidrug resistant areas. However, to ease administra-
tion in regions where P. falciparum is not multidrug
resistant, a four day regimen appeared to be equally
effective and cost saving. A head-to-head, double blind
study conducted by Van Vugt et al., examined the 28
day cure rate, with two six-dose regimens compared to
a four-dose regimen of Coartem in 359 patients. A 28
-day cure rate was defined as the proportion of pa-
tients with clearance of asexual parasitemia within 7
days of initiation of trial treatment, without subse-
quent relapse within 28 days after starting study treat-
ment The results showed that the six-dose admini-
stration schedule was more effective than the four-
dose regimen of Coartem in adolescents and adults
with uncomplicated P. falciparum malaria. 14 The 28-
day cure rates were 96.9% and 99.12% for the two six-
dose regimens compared to 83.3% for the four-dose
regimen (p < 0.001). Makanga et al, conducted a com-
parable study in children and infants (n=544) which
provided similar results.15 The corrected 28 day cure
rates were 93% and 96% compared to 61% and 76%

Ph m oeVlue2,Ise2 oebr20

Volume 25, Issue 2 1 November 2009


Table 1. Comparison of antimalarial drug therapy options.






Works synergistically to
inhibit the electron trans-
port & collapse the mito-
chondrial membrane

Inhibits DNA synthesis &
depletes folate cofactors

Interfere w/ lysosomal
degradation of Hb & di-
gestive function of malarial

Interferes w/ lysosomal
degradation of Hb & diges-
tive function of malarial

Inhibits replication of asex-
ual erythrocytic parasites
by raising pH & inhibiting
nucleic & protein synthesis

Disrupts replication & tran-
scription; depresses 02
uptake & carbohydrate

Treatment & prophy-
laxis of drug resistant
P.falciparum or
P. vivax

Treatment of
P.falciparum &
P. vivax when used
w/ Atovaquone

Treatment & prophy-
laxis for P. vivax,
P.ovale, P. malariae,
& CQ-sensitive
P. falciparum

Treatment & prophy-
laxis for P. vivax,
P.ovale, P. malariae,
& CQ-sensitive
P. falciparum

Prophylaxis of drug-
resistant P. falcipa-
rum or P. vivax

Treatment against CQ
-resistant P. falcipa-

atovaquone +

F: Readily absorbed
M: Hepatic
E: Urine
t%: 10-13 hrs: adult, 3
hrs healthy children, 12
hrs w/ malaria

A: 4 adult tabs po qd x 3 days

5-8kg: 2 peds tabs po qd x 3 d
9-10kg: 3 peds tabs po qd x 3 d
11-20kg: 1 adult tab po qd x 3 d
21-30kg: 2 adult tabs po qd x 3d
31-40kg: 3 adult tabs po qd x 3d
> 40 kg: 4 adult tabs po qd x 3d

F: Variable
M: Enterohepatic cir-
E: Feces
t%: 2-3 days: adults & 1
-2 days in children

F: Variable
M: Hepatic to active
E: Urine
t%: 12-21 hrs

F: Rapid
M: Partially hepatic
E: Urine
t%: 3-5 days

F: Rapid absorption
M: Hepatic
E: Urine
t%: 32-50 days

F: Well absorbed
M: Extensively hepatic
E: Bile & feces
t%: 21-22 days

A: 684 mg base po as initial dose,
followed by mg 456 base po given 6-
12 hrs after initial dose

P: 13.7 mg base/kg po as initial dose,
followed by 9.1 mg base/kg po given
6-12 hrs after initial dose.

A: 542 mg base po tid

P: 8.3 mg base/kg po tid
x 3 or 7 days

Abdominal pain
(17%), N/V (12%)

CNS, GI, CV, ocu-
lar, dermatologi-
cal disturbances

CNS, CV, derma-
tological & ocular

N/V (3%)

CNS, CV, photo-
sensitivity, mus-
cle weakness

CYP2D6 substrates, drugs that pro-
long QT interval

CYP 2D6 substrates, methotrexate,





Table 1 (continued). Comparison of antimalarial drug therapy options.


pyrimethamine +



Pyrimethamine inhibits
DHF reductase; Sulfadox-
ine inhibits dihydrop-
teroate synthase

Interferes w/ plasmodial

Slow acting blood schizon-

Used as adjunctive
therapy for CQ-
resistant P. falcipa-

Prophylaxis of drug-
resistant P. falcipa-
rum or P. vivax

Prophylaxis or ad-
junctive therapy for
CQ-resistant P. falci-

F: Well absorbed
M: Hepatic
E: Urine
t%: 80-95 hrs

F: Well absorbed
M: Hepatically to active
E: Urine
t%: 3-10 hrs

F: Rapid
M: Chelate formation
E: Urine & feces
t%: 12-15 hrs

A: 2-3 tablets pox 1

5-10 kg: Y tablet po x 1
11-20 kg: Y tablet po x 1
21-30 kg: 1 & Y2 tablets po x 1
31-45 kg: 2 tablets po x 1
>45 kg: 3 tablets po x 1

300mg base po every day for 14 days

A: 100 mg po bid x 7 days

P: 2.2 mg/kg po every 12 hrs x 7 days

syndrome, rash


syndrome, rash

A: Adult dose, CV: cardiovascular, E: elimination, F: oral bioavailability, M: metabolism, N/V: nausea & vomiting, P: Pediatric dose, tY,: half life
aCost per single tablet accessed from http://www.drugstore.com. Accessed 7/12/09
bMalarone: Adult tab = 250 mg atovaquone/ 100 mg proguanil; Peds tab = 62.5 mg atovaquone/ 25 mg proguanil
cUsed w/ doxycycline
dFansidar: Available as 25mg Pyrimethamine; 500mg Sulfadoxine



Table 2. Overview of Coartem(artemether/Iumefantrine).



Works synergistically to interfere with nucleic acid & protein synthesis

Treatment for drug-resistant P. falciparum


F: Rapid absorption
M: Hepatic
E: Urine
t%: 2-3 hours

F: Slower absorption
M: Hepatic
E: Feces
t%: 3-6 days




A 3-day treatment for a total of 6 oral doses for both adult & pediatrics. Patient should receive the
initial dose, followed by the second dose 8 hrs later, then 1 dose PO bid for the following 2 days.
S5 <15 kg: 1 tablet per dose
. 15 <25 kg: 2 tablets per dose
. 25 <35 kg: 3 tablets per dose
. >35 kg: 4 tablets per dose (total of 24 tablets)

. HA (56%)
. Palpitations (18%)
. N/V (17%)

$10.50 per tablet or $89.56 for 24 tablets (6 dose adult treatment)

E: elimination, F: oral bioavailability, M: metabolism, ty: half life, HA: headache, N/V: nausea & vomiting

(p < 0.0001) for the six-dose and four-dose regimen
Gametocyte reduction may be equally if not more
important than a 28-day cure rate for an active infec-
tion. Sutherland et al. investigated the amount of ga-
metocyte reduction between treatment with Coar-
tem or a combination of chloroquine (CQ)/
sulfadoxine pyrimethamine (SP). This single-blind,
randomized controlled trial was conducted in children
ages 1-10 with acute uncomplicated falciparum ma-
laria. Children were randomized to receive standard
doses (see Table 2) of either a combination of CQ/SP
(n= 91) or a six dose regimen of Coartem (n=406).
There is known resistance to chloroquine, so it was
combined with SP in attempt to extend its usefulness
since SP remains effective in 95% of this patient popu-
lation. The major endpoints were gametocyte carriage
rates, as well as the potential for children carrying ga-
metocytes 7 days post treatment to infect mosqui-
toes.16 Children treated with Coartem were signifi-
cantly less likely to carry gametocytes during follow-
up than children treated with CQ/SP (p < 0.001 at each
of days 7, 14, and 28; relative risk 6.15; 95% CI: 4.10-
9.23). Additionally, 28 days post treatment, children
treated with Coartem compared to CQ/SP carried
the parasites for a shorter time (0.3 and 4.2 days re-
spectively; p < 0.0001), and their blood was less able

to infect mosquitoes (p < 0.001). This study is signifi-
cant since it showed that while a treatment cure is im-
portant, it should be viewed only as the initial goal.
The second and equally important goal should be a
reduction in gametocyte carriage rates and therefore a
reduction in transmission of P. falciparum malaria in-
fections to surrounding regions.17
In the case where CQ & SP resistance is prevalent
and not the current standard of care, both amo-
diaquine plus SP and amodiaquine plus artesunate,
have been compared to Coartem to determine which
of these therapeutic options are more efficacious. A
single-blind, randomized clinical trial was conducted
in 329 Ugandan children ages 1-10.18 Patients were
randomized to treatment with standard doses of amo-
diaquine/SP (n= 111), amodiaquine/artesunate
(n=113), or Coartem (n=105).18 The primary out-
come was the 28 day risk of recurrent parasitemia
(early treatment, late clinical or late parasitological
failure). Primary outcomes were classified as: early
treatment failure (complicated malaria or failure to
respond to therapy on days 0-3), late clinical failure
(complicated malaria or fever and parasitemia on days
4-2), late parasitological failure (asymptomatic para-
sitemia on days 7-28), or adequate clinical and parasi-
tological response (absence of parasitemia on day 28).
Each episode of uncomplicated malaria was unad-

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Volume 25, Issue 2 1 November 2009


justed or adjusted by genotyping to distinguish be-
tween recurrence and a new infection. The secondary
outcomes measured change in gametocyte carriage
and hemoglobin levels. Additionally, hemoglobin lev-
els were measured to monitor anemia as a predictor of
malaria burden. 19
Results demonstrated that the unadjusted 28-day
risk of treatment failure for individual episodes of ma-
laria were 26.1% (95% CI, 21.1-32.1) for amo-
diaquine/SP, 17.4% (95% CI: 13.1-23.1) for amo-
diaquine/artesunate, and 6.7% (95% CI, 3.9-11.2) for
Coartem. Likewise, the risks of treatment failures
(adjusted by genotyping) due to recurrence, were sig-
nificant: 14.1% (95% CI: 10.3-19.2) for amodiaquine/
SP, 4.6% (95% CI: 2.5- 8.3) for amodiaquine/
artesunate, and 1.0% (95% CI: 0.3-4) for Coartem
(p< 0.008 for all pairwise comparisons, except amo-
diaquine plus artesunate vs Coartem p=0.05).
The changes in the hemoglobin levels from day 0
to day 14 were not significantly different between
treatment groups, however the prevalence of gameto-
cytes were lowest with Coartem (3.5%) compared to

amodiaquine/artesunate (6.1%) or amodiaquine/SP
(14% ) (amodiaquine/SP versus amodiaquine/
artesunate, p<0.05; amodiaquine/SP versus Coar-
tem, p<0.05). For both the primary and secondary
outcomes, Coartem was significantly more effective
as a treatment option against uncomplicated falcipa-
rum malaria.
Based on malarial resistance patterns, populations
exist where treatment options may be equally effec-
tive as Coartem. A randomized, open label study
conducted by Sagara et al, compared standard treat-
ment doses of artesunate-sulfamethoxypyrazine-
pyrimethamine (AS-SMP) given every 24 hours (n
=476), AS-SMP given every 12 hours (n=458), and the
6 dose treatment of Coartem (n=458).20The primary
endpoint was the 28-day cure rates and secondary
endpoints were early treatment failure, late clinical
failure, late parasitological failure, adverse events
(clinical and laboratory abnormalities), anemia
(hemoglobin value<10 g/dl), clearance rate of fever
and parasitemia, and gametocyte carriage.
Although no statistically significant difference ex-

Table 3. Summary of clinical trials for treatment of P. falciparum malaria infections.

Van Vugt, RDB 4 dose Coartem Primary: 28 day 6 dose > 4 dose regimen of Coartem w/ no difference
et al.14 (n=120) vs two 6 dose CR in tolerability & safety.
(1999) Coartem (n=118,
Sutherland, RC Chloroquine/ sul- Primary: 28 day Patients treated w/ Coartem less likely to carry game-
et al.16 phadoxine- CR tocytes 28 days following treatment than those receiving
(2005) pyrimethamine (n= Secondary: game- CQ/SP (p < 0.0001). Coartem > CQ/SP for gametocytes
91) vs. 6 dose Coar- tocyte carriage & densities, time (p < 0.0001) & infectious rate of mosqui-
tem (n=406) infectious rate of toes at day 7 (p < 0.001) vs. CQ/SP.
Dorsey G, RSB Amodiaquine/SP Primary: 28-day 28-day risk of treatment failure, unadjusted & adjusted
et al.'8 (n=111) & amo- risk of treatment for genotyping lowest for Coartem. Prevalence of ga-
(2007) diaquine/artesunate failure metocytes lowest w/ Coartem (amodiaquine/SP vs
(n=113) vs. 6 dose Secondary: Game- amodiaquine/artesunate, p < 0.05; amodiaquine /SP vs
Coartem (n=105). tocyte carriage Coartem, p < 0.05).
Sagara, ROL AS-SMP every 24hrs Primary: 28-day No difference in primary endpoints.
et al.20 (n =476), AS-SMP CR Incidence of vomiting was 7.0%, 4.6% and 2.2% for AS-
(2009) every 12hrs (n=458) Secondary: Inci- SMP 12 hr, AS-SMP 24 hr & Coartem group respec-
vs. 6 dose Coartem dence of AE tively. Incidence of diarrhea was 3.3%, 0.6% and 1.3% for
(n=450) the AS-SMP 12-hr, AS-SMP 24 hr & Coartem group re-
spectively .
Hatz, OL 128 patients treated Primary: 28-day 28 day CR was 96% (95% Cl 90.8-98.7). Gametocytes
et al.21 w/ 6 dose Coartem CR carriage reduced from 20.6% on days 0-3 to no gameto-
(2008) Secondary: Game- cytes present on days 8 to 42.
tocyte carriage
C: controlled; CR: cure rate; DB: double blind; OL: open label; R: randomized; SB: single blind

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ra ma ote

isted for primary endpoints, a higher incidence of side
effects, such as vomiting and diarrhea, was observed
in the AS-SMP 12 hour group. The incidence of vomit-
ing was 7.0% (n = 458), 4.6% (n = 476) and 2.2% (n =
450) for AS-SMP 12 hour group, AS-SMP 24 hour
group and Coartem group respectively. Additionally,
the incidence of diarrhea was 3.3%, 0.6% and 1.3% for
the AS-SMP 12-hour group, AS-SMP 24 hour group and
Coartem group respectively. While this confirms
that antimalarial treatment should be tailored accord-
ing to local drug sensitivity patterns, it also highlights
the importance of secondary factors in selecting ap-
propriate therapy. Patients on Coartem experienced
fewer side effects and were able to tolerate treatment
better than patients taking AS-SMP every 12 or 24
hours. Tolerability of anti-malarial treatments may
determine compliance and therefore efficacy and out-
come of treatment
While Coartem has been used extensively in en-
demic countries, it has also been shown to be effective
in non-immune travelers in an open-label, non-
comparative study, conducted by Hatz et al.21 Patients
were described as non-immune if they did not have an
acute P. falciparum infection diagnosed during the last
5 years and have either not spent long periods during
the 5 years before the study in malaria-endemic areas
or spent their first 5 years of their life in malaria-
endemic areas. These 124 patients were treated with
the standard six-dose regimen of Coartem. The pri-
mary endpoint, parasitological cure rate, was 96% at
the end of 28 days (95% CI 90.8-98.7). Gametocytes
were also reduced from 20.6% on days 0-3 to no ga-
metocytes present on days 8 to 42. Additionally, Coar-
tem was well tolerated with the main adverse events
reported as headache (29.1%), insomnia (13.3%) and
diarrhea (13.3%). However, these adverse events
were not compared to placebo and since these adverse
are commonly seen with malaria, they may merely be
signs or symptoms of malaria and not Coartem.
Table 3 summarizes the clinical trials for treat-
ment of P. falciparum malaria infections.


Travelers visiting malaria dense areas should take
necessary precautions to prevent from contracting
malaria. Preventative measures include wearing long
sleeve shirts and pants as well as using insecticides
when going outdoors. Long-lasting insecticidal nets
can also be used over bedding. Additionally, travelers
should determine what, if any, prophylaxis medication
are recommended based on the resistance patterns
within that country. Prophylaxis treatment must be
started before travel, and used continuously while

abroad, and for four weeks after leaving malaria-
endemic areas. Lastly, travelers should be counseled
on how to initiate treatment if they suspect malarial
symptoms such as unexplained persistent headaches,
weakness, vomiting, or diarrhea.

For additional information on traveling
precautions & malaria, visit CDC on the web:



Malaria is a preventable disease that has resulted
in nearly one million unnecessary deaths within the
last year. Monotherapy treatments with previously
established agents lead to the growing resistance of
nearly all parasitic forms, but most importantly P. fal-
ciparum. FDA-approved Coartem is currently effec-
tive in treating uncomplicated malaria due to P. falci-
parum in the United States although it has been used
worldwide for several decades. Although reducing
treatment time may reduce cost short term, care must
be taken to prevent facilitation of resistance.


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20. Sagara I, Rulisa S, Mbacham W et al. Efficacy and
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21. Hatz C, Soto J, Nothdurft H et al. Treatment of
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22. Centers for Disease Control. http://www.cdc.gov/
malaria/ Accessed July 29, 2009.

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Volume 25, Issue 2 i November 2009


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