Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00036
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Title: PharmaNote
Series Title: PharmaNote
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Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: November 2005
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Bibliographic ID: UF00087345
Volume ID: VID00036
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Alan Mumford, Pharm.D. Candidate

The importance of early, aggressive treatment
of lipid disorders following an acute coronary syn-
drome (ACS) is now well documented.1 Patients that
experience ACS are at high risk of suffering from
recurrent events. Patients who have experienced
ACS are 5 to 7 times more likely to have another
ischemic event than a person without such history.2
Consequently, secondary prevention of coronary
heart disease (CHD) must be considered early after
ACS. The Adult Treatment Panel III (ATP III)
Guidelines were recently updated by the National
Cholesterol Education Program (NCEP). The docu-
ment advocates a more aggressive approach to low-
ering of low density lipoprotein cholesterol (LDL-C)
than ever before. The update supports early, aggres-
sive lowering of LDL-C with hydroxymethyl glu-
taryl coenzyme A (HMG-CoA) reductase inhibitors
stations ) in patients with ACS, as well as other pa-
tient populations, such as patients with multiple un-
controlled risk factors.4 This article will explore the
rationale for early, aggressive LDL-C lowering in
ACS patients in the context of the ATP III update.

Pathophysiological Basis of Achieving Lower
Ironically, the value of achieving lower LDL-
C targets by way of higher station doses may be as
much related to pleiotropic effects of stations as to

actual LDL-C reduction. This is especially true given
the diminishing returns of doubling a station dose, an
event that only confers an additional 7% reduction in
LDL-C. Thus, the maximum attainable reduction in
LDL-C that can be achieved by increasing the dose
of a station is 21% if the dose is increased from 10 mg
to 80 mg.5 This observation highlights the concept
that stations may be reducing events at higher doses
independent of their effects on LDL-C
Atherosclerotic disorders start with the reten-
tion of (LDL-C) in the sub-endothelial space of arter-
ies. Once in the sub-endothelial space, LDL-C be-
comes oxidized, recruiting macrophages to the site,
which are then able to oxidize LDL-C at an acceler-
ated rate.2 When LDL-C is oxidized it has four po-
tentially detrimental functions. First, it increases tis-
sue plasminogen activator inhibitor (PAI-1), leading
to increased coagulation. Second, oxidized LDL-C
induces the expression of endothelial vasoconstric-
tive substances.2 Third, it inhibits the expression of
nitric oxide, a potent vasodilator and platelet inhibi-
tor. Lastly, it may promote macrophage cell death.
Large cholesterol-rich reservoirs called "foam cells"
eventually develop.2 Stored beneath the endothelial
layer, oxidized cholesterol derivatives provoke an
inflammatory response, causing the release of cyto-
kines that further worsen the inflammatory response.







Volume 21, Issue 2 November 2005


Eventually, the endothelial layer may rupture, expos-
ing highly oxidized cholesterol and other substances
that are strong initiators of platelet aggregation. The
downstream consequence is myocardial ischemia and
if unabated, infarction may occur. Independent of
their effects on cholesterol, stations exhibit anti-
inflammatory activity, they favorably modify throm-
botic balance, and stabilize the vascular endothelium.
It is these pleiotropic actions that serve as the basis
for aggressive dosing of stations for ACS.

Pleiotropic Effects of Statins
The treatment of choice for hyperlipidemia in
most patients with or without a history of ACS are
stations. Statins significantly decrease total mortality.
Statins provide the greatest degree of LDL-C lower-
ing, with minimal increases in high density lipopro-
tein cholesterol (HDL-C), and decrease triglyc-
erides.1 (Table 2)
Recently the pleiotropic effects of stations
have been documented. Atherosclerotic disorders
stem from inflammatory processes reacting to oxi-
dized LDL-C particles.3 In the PRINCE study, re-
searchers found that pravastatin therapy caused a de-
crease in high-sensitivity C-reactive protein (hs-
CRP) (a clinical marker of inflammation). Further-
more, it was demonstrated that decreases in hs-CRP
were associated with a lower incidence of ACS.3 The
REVERSAL trial supported these conclusions by
showing that a decrease in hs-CRP by at least 2 mg/L
was associated with a significant decrease in athero-
sclerotic progression. Thus, the anti-inflammatory
effect of stations may be as important as the ability to
lower LDL-C levels, especially around the time of an
acute event.3
Statins also improve vascular endothelial
function. Atherosclerosis involves vascular dysfunc-
tion, which manifests as an imbalance between nitric
oxide (NO), a local vasodilator, and endothelin-1
(ET-1), a vasoconstrictor, leading to a state of en-
hanced vasoconstriction. Notably, this imbalance is
most often seen in patients that have diabetes melli-
tus, hypertension, elevated LDL-C, elevated homo-
cysteine levels, or smoke cigarettes. 3 Statins function
to restore balance by increasing nitric oxide, decreas-
ing ET-1, or both. 3
An additional action of the stations is plaque
stabilization. ACS usually begin with plaque rupture
and exposure of subendothelial substances to plate-
lets and other thrombotic mediators. Plaques rupture
when inflammatory cells (mainly macrophages) re-

lease proteolytic enzymes from within the plaque
leading to a breach of the intima tunica.3Almuti et al.
described the stations' role in interfering with several
functions of these inflammatory cells. These actions
include inhibiting the inflammatory cells from adher-
ing to the vascular endothelium, trans-migrating into
tissue, or secreting pro-inflammatory cytokines and
free radicals.3
In addition to these pleiotropic benefits of
stations, there have been additional findings to support
their use. Overproduction of smooth muscle cells in
the intimal layer of blood vessels contributes to
artherosclerosis. Statins interfere with these proc-
esses by blocking the effects of growth factors while
at the same time promoting NO production. In addi-
tion, patients with atherosclerosis are at increased
risk of platelet aggregation due to accelerated pro-
duction of thromboxane A2.3 Finally, stations have
been shown to decrease the oxidation of LDL-C,
which prevents the attraction of macrophages.3

Update to the ATP III Guidelines
In September 2004 the ATP III guidelines
were updated to address the publication of landmark
studies in the field of hyperlipidemia. One of the ma-
jor implications of the updated guidelines is the sup-
port of more aggressive lipid-lowering in high risk
The updated ATP III guidelines suggest that
an LDL-C goal of <70mg/dL is a therapeutic option
in very high risk patients.4 (Table 1) The decision of
when and where to implement the goal is left to prac-
titioners who must exercise clinical judgment given
a specific patient scenario.

Appropriate Dosage Selection
Statins are clearly established as first-line
therapy for elevated LDL-C due to their lipid lower-
ing potential as well as their pleiotropic benefits.
However, it is important to realize that while all stat-
ins are thought to share these pleiotropic effects, they
do not all exhibit the same potency as lipid lowering
agents. The ATP III guidelines suggest lowering
LDL-C levels by at least 30 to 40% since this level
of LDL-C reduction is consistent with clinical trial
data. Thus, in order to achieve this decrease in LDL-
C a "standard minimum dose" has been identified for
each agent, to help clinicians select an evidence
based dose of a station needed to achieve the desired
decrease in LDL-C. Table 2 shows the relative po-
tencies of the stations at the "standard" dose identified

PharmaNote Volume 21, Issue 2 November 2005

Volume 21, Issue 2 November 2005


Table 1. Patients at very high risk of CHD events.4
Multiple major risk factors (especially diabetes mellitus)
Cigarette smoking

Metabolic Syndrome
(especially with concurrent triglycerides of 200mg/dL or
greater, non-HDL-C of 130 or greater, and HDL-C less or
equal to 40mg/dL.)

Patients with acute coronary syndromes

in the guidelines. In most cases, this should be con-
sidered the lowest effective dose of a station, with ef-
fective being defined as the lowest dose supported by
the literature.

Clinical Trial Data
The Pravastatin or Atorvastatin Evaluation
and Infection Trial (PROVE IT) was a randomized
treatment-controlled trial comparing pravastatin 40
mg with atorvastatin 80 mg. The primary endpoint
was a composite of all-cause mortality, unstable an-
gina, revascularization, MI, and stroke in patients
recently hospitalized with ACS. The trial followed
4,162 patients for 2 years. Of these patients, 75% had
never been treated with a station prior to enrollment.
In the 75% of patients that had never been treated
with a station, LDL-C levels decreased by 22% in the
pravastatin arm and 51% in the atorvastatin arm after
30 days (p<0.001). The remaining 25% had been on
station therapy previously, and experienced a virtually
unchanged LDL-C level in the pravastatin arm, but
experienced an additional 32% decrease in LDL-C in
the atorvastatin arm (p<0.001). The average LDL-C
level achieved after therapy was 95 mg/dl in the
pravastatin arm and 62 mg/dl in the atorvastatin arm.
After the two year follow-up, the primary endpoint
was reduced by an additional 16% in the atorvastatin
group compared to the pravastatin group (p<0.005).
In summary, aggressive station therapy conferred a

greater overall benefit in this patient population com-
pared with conventional station dosing. There was no-
cases of rhabdomyolysis and no increase in the rate
of discontinuation of therapy due to side effects.6 The
rate of liver function test elevations to greater than 3
times the upper limit of normal was significantly in-
creased in the atovastatin arm (3.3% vs. 1.1%,

AtoZ Trial7
The A to Z Trial was a randomized, double-
blind study using two different doses of simvastatin
in post-MI patients. The primary endpoints were car-
diovascular death, MI, hospital readmission for ACS,
and stroke. Patients received either 40 mg/day of
simvastatin for one month followed by 80 mg/day
(40/80) thereafter, or placebo for four months fol-
lowed by 20 mg/day (0/20) of simvastatin thereafter.
This study was comprised of 4,497 patients. In the
simvastatin 0/20 group there was a 31% decrease in
LDL-C. In the simvastatin 40/80 group, the median
LDL-C level decreased by 39%, with an additional
6% decrease after boosting the dose to 80 mg/day.
The primary end points occurred in 16.7% of the pla-
cebo plus simvastatin patients compared with 14.4%
in the simvastatin only group (p= NS). In this trial
there were 10 cases of myopathy (9 in the simvas-
tatin 40/80 arm), including 3 cases of rhabdomyoly-
sis (all in the simvastatin 40/80 arm), which suggests
that caution may be warranted with 80 mg dose sim-

The Myocardial Ischemia Reduction with
Aggressive Cholesterol Lowering (MIRACL) trial
was a prospective, randomized, multi-center, pla-
cebo-controlled clinical trial, which tested the ability
of high dose atorvastatin to prevent recurrent
ischemic events in patients with unstable angina or
non-Q wave myocardial infarction (NSTEMI). More

Table 2: Comparison of the currently available stations5' 7
fluvastatin lovastatin* pravastatin* simvastatin atorvastatin rosuvastatin
Drug (Lescol) (Mevacor) (Pravachol) (Zocor) (Lipitor) (Crestor)
Standard Dose ** 40-80mg 40mg 40mg 20-40mg 5-10mg 5mg
Increase in HDL at -7% -7%
~7% ~7%
standard dose
Decreasein LDL-Cat 25-35% 31% 34% 35-41% 39-45% 34%
Standard dose
Dosages available 20-80mg 10-60mg 10-80mg 5-80 mg 10-80mg 5-40mg
*Potencies increase moving from left to right with the exception of lovastatin and pravastatin, which are equipotent
**Standard dose is the dose required to achieve a approximate decrease in LDL-C of 30 to 40%

PharmaNote Volume 21, Issue 2 November 2005

than 3,000 patients hospitalized over 43 months for
unstable angina or non-Q wave MI with concurrent
cholesterol levels <270 mg/dL were enrolled. Pa-
tients were randomized within 96 hours of hospital
admission to atorvastatin 80 mg or placebo and all
patients were encouraged to follow NCEP Step One
Diet. While baseline cholesterol levels were equal in
the treatment and placebo group, by the end of the
study LDL-C declined 40% in the atorvastatin arm.
The primary endpoint of the MIRACL trial was the
time to first event, including all-cause death, resusci-
tated cardiac arrest, nonfatal MI, or worsening an-
gina pectoris with new objective evidence of myo-
cardial ischemia requiring urgent re-hospitalization.
The secondary endpoints were stroke, cardiac revas-
cularization, worsening congestive heart failure, or
worsening angina without objective evidence of
ischemia. A primary endpoint event occurred in
17.4% of patients in the placebo group and 14.8% of
patients in the atorvastatin group (p=0.48). This
translates to a 2.6% absolute risk reduction and 16%
relative risk reduction. Of the secondary endpoints,
notably, stroke was reduced by 50% in the atorvas-
tatin group (p=0.045), but other secondary endpoints
did not differ significantly between the groups.8

Clinical trial evidence supports the early, ag-
gressive dosing of stations in an effort to decrease
morbidity related to atherosclerotic disease. Statins
are currently the drug of choice for treating hyperlip-
demia due to their ability to decrease LDL-C and
their pleiotropic effects. Future studies should help
to identify optimal LDL-C thresholds for patients at
different levels of risk for cardiovascular disease.

1. Executive Summary of The Third Report of The National
Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, And Treatment of High Blood Cho-
lesterol In Adults (Adult Treatment Panel III). JAMA
2. Dipiro JT, Talbert RL. Pharmacotherapy: a Pathophysiologic
Approach. 5th Edition. McGraw-Hill, New York, 2002. pp
3. Almuti K et al. Effects of stations beyond lipid lowering: Po-
tential for clinical benefits. International Journal of Cardiol-
ogy. 2005. E published ahead of print available at:
4. Grundy et al. Implications of Recent Clinical Trials for the
National Cholesterol Education Program Adult Treatment
Panel III guidelines. Circulation 2004;110:227-239.
5. Roberts WC. The Rule of 5 and the Rule of 7 in Lipid Low-

ering Statin Drugs. American Journal of Cardiology
6. Cannon, CP. et al. Pravastatin or Atorvastatin Evaluation and
Infection Therapy-Thrombolysis in Myocardial Infarction
22 Investigators. Intensive versus Moderate Lipid Lowering
with Statins After Acute Coronary Syndromes (PROVE IT).
NEJM 2004;350:1495-1504.
7. De Lemos JA et al. Early intensive vs a delayed conserva-
tive simvastatin strategy in patients with acute coronary syn-
dromes: phase Z of the A to Z trial. JAMA 2004;292:1307-
8. Schwartz G et al. Effects of Atorvastatin on Early Recurrent
Ischemic Events in Acute Coronary Syndromes: The
MIRACL Study. JAMA 2004;285:1711-1718.


Dana Stripling, Pharm.D. Candidate

Immunocompromised patients are extremely
susceptible to invasive fungal infections. Over the
last few decades, fungal infections have increased
both in frequency and severity. Many factors con-
tributed to this increase, including advances in im-
munosuppressive therapy, decreased mortality, and
the widespread use of antibiotics.3 Invasive fungal
infections increase mortality in hospitals and are esti-
mated to cost the US health care system $25,000 per
episode with the total cost exceeding $300 million.4
Candida spp. are responsible for up to 8% of central
venous catheter-related blood stream infections.4 It is
estimated that 15% of allogeneic hemopoietic stem
cell transplant recipients develop an infection and
about 20% of AIDS patients develop esophageal can-
didiasis.3 Clearly, the projected increase in fungal
infections is of clinical importance.
Traditionally, several antifungals have been
used when treating invasive fungal infections. Am-
photericin B disrupts the fungal cell membrane by
binding to ergosterol. The azoles (fluconazole and
itraconazole) inhibit the synthesis of ergosterol.
However, resistance to these agents is increasing. It
has been reported that in the US, 10% of C. albicans
causing bloodstream infections were resistant to flu-
conazole.4 Of even greater concern, is that 48% of
candidal bloodstream infections were associated with

PharmaNote Volume 21, Issue 2 November 2005

Volume 21, Issue 2 November 2005


Table 1. Spectrum of micafungin activity. 1,3,4
Invasive aspergillosis (fungistatic)
Indicated for infections caused by: Candida albicans (including azole-resistant strains) (fungicidal)
Non-albicans Candida
The mycelial form of H. capsulatum
Also active against: B. dermatitidis
C. immitis
Nt a e a : Cryptococcus neoformans
Not active against: Fusarium

non-albicans species like C.glabrata and C. krusei.4
These species are more likely to be resistant to azoles
than C. albicans.4 With resistance to azoles on the
rise and the adverse effects of ampotericin B, the
need for new drugs is apparent. Micafungin
(Mycamine TM) is a novel antifungal agent that
works by inhibiting the production of B- (1,3)-D-
glucan, which is important to fungal cell wall synthe-
sis. It was developed because of the need for safe,
broad-spectrum antifungals with few drug interac-
tions. Mycamine T was identified in 1990. The FDA
approved it on March 16, 2005. It is co-marketed by
Fujisawa Healthcare, Inc., its manufacturer, and
Roche Pharmaceuticals. Micafungin is indicated for
the treatment of esophageal candidiasis and for the
prophylaxsis of Candida infections in patients under-
going hematopoietic stem cell transplantation. The
objectives of this article are to review the efficacy,
safety, and place of micafungin in antifungal phar-

Pharmacology and Pharmacokinetics
Micafungin, a large water-soluble lipopep-
tide, is a cell wall synthesis inhibitor belonging to the
echinocandin class.1 It is derived from chemical
modification of the mould, Coleophoma empedri.
Micafungin has a complex aromatic side chain (3,5-
diphenyl-substituted isoxazole) that distinguishes it
from the other echinocandins.3 It inhibits the synthe-
sis of B- (1,3)-D-glucan which is an essential compo-
nent of the fungal cell wall.1-2 This inhibition causes
changes to the cell wall resulting in osmotic stress,
lysis and eventual cell death. Because B- (1,3)-D-
glucan is not present in mammalian cells, micafungin
poses a low risk for mechanistic toxicity in humans.1-
2 Micafungin is fungicidal against Candida spp., in-
cluding isolates resistant to fluconazole and itracona-
zole, and has potency against clinical isolates of As-
pergillus spp.1 (Table 1).


Due to its poor oral bioavailability, mica-
fungin is only available in an intravenous formula-
tion.1-2 It has a small volume of distribution and is
highly protein bound (99%). However, only a small
amount is bound to albumin.3 Micafungin is not dia-
lyzable. The mean half-life of micafungin is 13
hours.7 Steady state concentrations are reached after
approximately four days of treatment.3 Fecal excre-
tion is the major route of elimination.8 Micafungin is
metabolized in the liver by hydrolysis and N-
acetylation.3 It has fewer drug interactions than the
azoles because it is a poor substrate for CYP450 en-
zymes and P-glycoprotein. However, micafungin has
been shown to increase systemic exposure to si-
rolimus by 21% and nifedipine by 18%. 2 It has been
noted by some researchers that this drug has in-
creased uptake by red blood cells. 3 Micafungin has
two metabolites that have antifungal activity; they
are mainly excreted in the bile over several days.3
There is no antagonism between echinocandin-azole
or echinocandin-amphotericin B combinations. In
fact, there may be an additive or synergistic effect.
Studies have indicated that micafungin has no clini-
cally relevant interactions with cyclosporin or tac-

Clinical Trials
Several studies have investigated the efficacy
of micafungin in esophageal candidiasis and for pro-
phylaxis of fungal infections in adult patients under-
going bone marrow or peripheral stem cell trans-
plants. One study explored the pharmacokinetics and
maximum tolerated dose of micafungin in combina-
tion with fluconazole versus fluconazole alone. An-
other study compared the efficacy and safety of mi-
cafungin vs. fluconazole for the treatment of eso-
phageal candidiasis. Also, the minimum effective
dose and safety of micafungin for the treatment of
HIV-related esophageal candidiasis was evaluated.

Volume 21, Issue 2 November 2005

Table 2. Clinical studies of micafungin. 5,6,7
Study Demographics N Design (mg/day) Result
1. *Defined minimum ef-
SHIV-related esophageal OL study of the effects fective dose to be 12.5
Pettengell et al. -re esopagea 120 50
candidiasis ofM mg
1 *Well tolerated and safe
M: 12.5
25 *M+F deemed safe
Prophylactic antifungal RD, 50 *Indicates that the maxi-
RDB, dose escalation, isao
Hiemenz et al.7 therapy after bone mar- 74 tolerance study of M +dose ofM is above
row or stem cell trans- 100 200mg/day
plantation vs150 *Doses up to 200mg/day
200 were well-tolerated
F: 400
6 Esophageal M: 150 *M is an efficacious and
De Wet et al. candidiasis 523 RDB, study of M vs. F200 safe alternative to F
M micaungin candidiasisazoF: 200 safe alternative to FR
M= micafungin, F= fluconazole, OL= open label, RDB= randomized double blind

The results from these studies are summarized in Ta-
bles 2 and 3 and the ensuing section.

HIV-related esophageal candidiasis
Pettengell et al. 5 determined the clinical
safety and efficacy of micafungin in patients with a
documented Candida infection. The minimum effec-
tive dose of micafungin in patients with HIV-related
esophageal candidiasis was evaluated. One- hundred
and twenty patients were recruited for this open-label
study. The patients consisted of men and women
over the age of eighteen with a diagnosis of HIV.
Esophageal candidiasis was confirmed by endo-
scopy. The patients were administered daily one-
hour infusions of micafungin and were randomly as-
signed to doses of 12.5, 25, 50, 75, and 100 mg. The
minimum effective dose was defined as the lowest
dose achieving clinical cure or improvement in at
least 65% of patients after 10 days of therapy. Pa-
tients were evaluated at baseline and on days 3, 7,
and 14 after the start of micafungin, and at 2 weeks
post treatment. The primary outcome measured was
defined as cure or improvement of signs and symp-
toms. The secondary outcome measures were im-
provement in esophageal mucosal lesions, mycologi-
cal response, the rate of relapse in the 2 weeks post-
treatment, quantitative clinical assessments, and the
overall therapeutic success.
Each dosing group had a positive clinical re-
sponse except one patient in the 12.5 mg group. A
decrease in symptoms was demonstrated within 3 to
5 days of treatment. There was a noticeable dose-
response relationship, which was statistically signifi-

cant (p = 0.001). With respect to mucosal lesions, the
75 mg and 100 mg doses were superior based on a 2
to 3 fold greater decline from baseline. The 12.5 mg
dose was deemed the minimum effective dose. Ad-
verse events attributed to micafungin occurred in
29.2% of patients. The most frequent adverse effects
were vomiting (6.7%), liver function test abnormali-
ties (5.8%), nausea (5.0%), and rash (3.3%). There
were no cases of nephrotoxicity or infusion-related
reactions. Histamine-like reactions and hepatotoxcic-
ity were not observed. Micafungin was well tolerated
and effective in this study and the results were com-
parable to other drugs used to treat esophageal can-

Comparative trial of micafungin vs. fluconazole
A randomized, double blind, multicenter,
multinational trial of micafungin versus. fluconazole
was conducted by De Wet et al.6 The study involved
523 patients, age 16 or older, with documented eso-
phageal candididasis. Each patient either received
intravenous micafungin (150 mg per day) or intrave-
nous fluconazole (200 mg per day). The drug was
administered as a 1-hour infusion once a day for a
minimum of 14 days or for 7 days after successful
elimination of the signs and symptoms of the infec-
tion. At the end of therapy, a mucosal grade of zero
was defined as treatment success and was the pri-
mary outcome. The frequency of relapse at 2 and 4
weeks post treatment, the change in mucosal grade,
and overall therapeutic response (improvement) were
secondary endpoints. Micafungin patients had an
87.7% endoscopic cure rate, whereas fluconazole

PharmaNote Volume 21, Issue 2 November 2005

Volume 21, Issue 2 November 2005


Table 3. Adverse reactions. 5,6,7
Study Adverse Reactions
Vomiting (6.7%)
Pettengell et Liver function test abnormali-
Pettengell et al. t (.%
ties (5.8%)
(N 120) Nausea (5.0%)
Rash (3.3%)

Headache (6.8%)
Hiemenz et Arthralgia (6.8%)
z et a. Maculopapular rash (4.1%)
(N= 74) Rash (4.1%)
Hypophosphatemia (4.1%)
Insomnia (4.1%)

De Wet et al.6 Rash (3 patients)
Rash + delirium (1 patient)
(N= 523) Delirium (1 patient)

had an 88% endoscopic cure rate (95% CI, -5.9 to
5.3). Patients treated with either medication im-
proved within 3 to 5 days of starting therapy. Flu-
conazole reported an 87.2% overall therapeutic suc-
cess rate and micafungin reported an overall thera-
peutic success rate of 87.3% (95% CI, -5.6 to 5.8).
The frequency of drug related adverse events were
27.7% for micafungin and 21.3% for fluconazole (p
= 0.102). Rash (three patients), rash and delirium
(one patient), delirium (one patient), and AIDS pro-
gression (one patient) led to the discontinuation of
micafungin. In the case of fluonazole, there were two
patients who discontinued the medication: one due to
rash and one due to asthenia and delirium. Treatment
success and relapse rates were comparable with the
two medications. Micafungin had a relapse rate of
15.2% versus 11.3% with fluconazole through week
4 (p > 0.25). One disadvantage of micafungin is that
it can only be dosed intravenously; however, oral
medications are often hard for HIV/AIDS patients to
take especially those who have mucosal lesions.

Micafungin in combination i/h fluconazole vs. flu-
conazole alone
A pharmacokinetic and maximum tolerated
dose study was performed by Hiemenz et al.7 This
study compared micafungin in combination with flu-
conazole versus. fluconazole alone for prophylaxis of
fungal infections in adult patients undergoing a bone
marrow or peripheral stem cell transplant. Seventy-
four patients were chosen to participate in this ran-
domized, double blind, dose escalation, and tolerance

study. The patients received either fluconazole (400
mg/day) with micafungin (8 patients at each dose
level) or fluconazole (400 mg/day) with normal sa-
line (control group). The doses used for micafungin
were: 12.5, 25, 50, 75, 100, 150, 200 mg/day. The
patients consisted of men and women between the
ages of 18 and 55 years old who had underwent a
bone marrow or peripheral stem cell transplant.
Treatment was started between 48 hours prior to
transplant and 24 hours post transplant. Fluconazole
was given either by mouth, the preferred route, or by
intravenous infusion. Micafungin was given by intra-
venous infusion of 100 ml over 1 hour. There were
four patients in the micafungin treatment group who
developed a grade three or greater toxicity. Three of
these events occurred at the 150 mg and 200mg
doses. However, the criterion for the maximum tol-
erated dose was not met, indicating that the maxi-
mum dose in this study is within the range of doses
that merit further study. The frequency of adverse
events between the control group and the mica-
fungin-fluconazole groups were not clinically signifi-
cant. There were several events possibly related to
micafungin: headache (6.8%), arthralgia (6.8%), hy-
pophosphatemia (4.1%), insomnia (4.1%), maculo-
papular rash (4.1%), and rash (4.1%).7 No reports
were made of infusion-related reactions. There were
no dose-limiting toxicities noted. The pharmacoki-
nectic profiles of micafungin on days one and seven
were comparable. From zero to twenty-four hours,
the mean maximum concentrations of the drug in
serum and area under the concentration time curve
were relatively proportional. Several patients had a
possible fungal infection by the end of treatment:
41.7% of patients in the control group compared with
22.6% of patients in the micafungin-fluconazole
group (regardless of micafungin dose).
Overall, micafungin in combination with flu-
conazole was safe in this patient population. Doses
up to 200 mg/day were safe. Gender and race appear
to have no effect on outcomes. Drug interactions be-
tween micafungin and fluconazole were absent. Fur-
ther research is warranted to elucidate whether the
combination is safe and effective for the prevention
of fungal infections in patients undergoing bone mar-
row or peripheral stem cell transplants.

Dosing and Administration
An advantage of micafungin is that it can be
dosed once daily by intravenous infusion. However,

Phrm~oe olme21 sse Nvebe 20

Volume 21, Issue 2 November 2005


Table 4. Cost analysis. 8
Drug Mg/Day AWP/Day
Micafungin 150 mg $280.50

Caspofungin 50 mg $372.68
Amphotericin B 18.75-75 mg $11.64-$23.28
Fluconazole Oral 100-200 mg $9.39-$15.36
Fluconazole IV 100-200 mg $110.97

AWP average wholesale price.

there is no oral formulation. There are several start-
ing doses recommended with dose escalation permit-
ted: for invasive aspergillosis 75 mg/day (1.5 mg/
kg/day if weight <40 kg), for Candida albicans- 50
mg/day (1 mg/kg/day if weight <40 kg), and for
Non-albicans Candida spp.- 100 mg /day (2 mg/kg/
day if wt under <40 kg). 4 For candidiasis prophy-
laxis in hematopoietic stem cell transplant patients, a
dose of 50 mg/day as an IV infusion over one hour
should be administered. The duration of treatment in
clinical trials was between 6 and 51 days with a
mean of 19 days.2For the treatment of esophageal
candidiasis, 150 mg/day administered as an IV infu-
sion over one hour is recommended. The treatment
duration was between 10-30 days.2 The safety and
efficacy has not been established in infants, children,
or adolescents. There are no dosage adjustments
needed in patients who have renal impairment or
who have mild to moderate hepatic impairment.2
There is no data on patients with severe hepatic im-
pairment. Micafungin is not dialyzable so supple-
mental dosing is not necessary.2

Table 4 depicts pricing for micafungin and
other frequently used antifungal agents.

Fungal infections are increasing at an alarm-
ing pace. Micafungin is a new antifungal indicated in
the treatment of esophageal candidiasis and for the
prophylaxis of Candida infections in patients under-
going hematopoietic stem cell transplantation. With
resistance to the azoles on the rise and the nephro-
toxic effects of Amphotericin B, micafungin could
be a useful alternative. It is well- tolerated with no
apparent dose related adverse effects. Micafungin
does not cause a histamine-like reaction like other

drugs in its class (eg., caspofungin). It has few drug
interactions and may be synergistic with azoles or
amphotericin B. Bilirubinemia, nausea, vomiting,
diarrhea, and increased liver function tests have been
the most common adverse effects. Additional studies
are required to establish the role of micafungin in
practice. Ideally, studies comparing micafungin with
caspofungin will be conducted.

1) Boucher HW et al. Newer systemic antifungal agents.
Drugs 2004; 64:1997-2020.
2) Clinical Pharmacology [monograph]. Gold Standard Me-
dia. Version 2.16. Tampa: April 2005
3) Denning DW. Echinocandin Antifungal Drugs. Lancet
4) Jarvis B et al. Micafungin. Drugs 2004;64:969-982
5) Pettengell K et al. Successful treatment of oesophageal
candidiasis by micafungin: A novel systemic antifungal
agent. Aliment Pharmacol Ther 2004;20:475-481.
6) De Wet NTE et al. A randomized, double blind, compara-
tive trial of micafungin (FK463) vs. fluconazole for the
treatment of oesophageal candidiasis. Aliment Pharmacol
Ther 2005;21:899-907.
7) Hiemenz J et al. Pharmacokinetic and maximum tolerated
dose study of micafungin in combination with fluconazole
verses fluconazole alone for prophylaxis of fungal infec-
tions in adult patients undergoing a bone marrow or periph-
eral stem cell transplant. Antimicrobial Agents and Chemo-
therapy 2005;49:1331-1336
8) Crouch W et al. Micafungin. University of Utah Hospitals
and Clinics. Drug Information Services 2005. Available:
http://uuhsc.utah.edu/pharmacv/druginfo. Accessed: 9/05.

The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida

John G. Gums Editor

R. Whit Curry, M.D. Associate Editor

Benjamin J. Epstein Assistant Editor


Volume 21, Issue 2 November 2005


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