Title: PharmaNote
ALL VOLUMES CITATION PDF VIEWER THUMBNAILS PAGE IMAGE ZOOMABLE
Full Citation
STANDARD VIEW MARC VIEW
Permanent Link: http://ufdc.ufl.edu/UF00087345/00010
 Material Information
Title: PharmaNote
Series Title: PharmaNote
Physical Description: Serial
Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: April 2003
 Record Information
Bibliographic ID: UF00087345
Volume ID: VID00010
Source Institution: University of Florida
Rights Management: All rights reserved by the source institution and holding location.

Downloads

This item has the following downloads:

April2003 ( PDF )


Full Text















EZETIMIBE (ZETIA):
A NOVEL LIPID-LOWERING
AGENT

Mohammed Aide, Pharm.D. Candidate


Introduction
Hypercholesterolemia involves the exis-
tence of large quantities of cholesterol in the cells
and blood plasma. It is caused by a disturbance in
the lipid transport process that results from in-
creased lipoprotein synthesis or decreased lipopro-
tein degradation. These lipoproteins are responsible
for transporting cholesterol and triglycerides (TG)
in the plasma. The two major classes of lipopro-
teins are low-density lipoproteins (LDL) and high-
density lipoproteins (HDL). An estimated 100 mil-
lion adults in the United States have total-
cholesterol levels above normal (= 200mg/dL).1 Of
those, 40 million have levels that are = 240mg/dL.1
Reduction of LDL cholesterol is a key approach for
lowering the risk of coronary heart disease (CHD),
resulting in reduced cardiovascular morbidity and
mortality.2 The FDA approved Zetia (ezetimibe)
in October 2002 as a new oral treatment for hyper-
cholesterolemia. Merck/Schering-Plough Pharma-
ceuticals are marketing the drug in the United
States.
Ezetimibe is a novel selective inhibitor of
intestinal cholesterol absorption from dietary and
biliary sources without affecting the absorption of
fat soluble vitamins and triglycerides.3'4 Ezetimibe
alone is indicated as adjunctive therapy to diet and
exercise for the reduction of total cholesterol
(Total-C), LDL, and apolipoprotein B (Apo B) in
patients with primary hypercholesterolemia and


the reduction of elevated sitosterol and campesterol
levels in patients with homozygous sitosterolemia.
It is also indicated in combination with an HMG-
CoA reductase inhibitor for the reduction of ele-
vated total-C, LDL, and ApoB in patients with pri-
mary hypercholesterolemia and homozygous famil-
ial hypercholesterolemia. This article will discuss
the pharmacology, pharmacokinetics, clinical trials,
adverse effects, and cost of ezetimibe.

Pharmacology
Ezetimibe decreases blood cholesterol by
inhibiting the absorption of cholesterol by the small
intestine. Unlike other cholesterol-lowering com-
pounds, ezetimibe does not inhibit cholesterol syn-
thesis in the liver nor does it increase bile acid ex-
cretion. Ezetimibe acts at the brush border of the
small intestine to inhibit the absorption of choles-
terol leading to a reduction in the amount of choles-
terol delivered to the liver. This in turn causes a re-
duction of hepatic cholesterol stores and an in-
crease in cholesterol clearance from the blood
which makes ezetimibe use an appropriate adjunct
to HMG-Co A reductase inhibitors.

Pharmacokinetics
Ezetimibe is available as 10mg tablets. The
recommended dose of ezetimibe is 10mg once daily
without regard to meals for all its approved indica-
tions. Within 4-12 hours of the oral administration
of a 10mg dose to fasting adults, the attained mean
ezetimibe peak plasma concentration (Cmax) was
3.4-5.5 ng/ml.5 Following oral administration,
ezetimibe is absorbed and extensively conjugated
to a phenolic glucuronide (active metabolite). Mean
Cmax (45-71 ng/ml) of ezetimibe-glucuronide
are attained within 1-2 hours.5 The concomitant
administration of food (high-fat vs. non-fat meals)


m
Pha rma Note Volume 18, Issue 7 April 2003


SPharmaNote


VOLUME 18, ISSUE 7 APRIL 2003
tlL


PharmaNote


Volume 18, Issue 7 April 2003







Table 1. Response to ezetimibe in patients with primary hypercholesterolemia after 12 weeks meana % change from un-
treated baselineb5

Study Treatment Group N Total-C LDL ApoB TGa HDL

Study 1 Placebo 205 +1 +1 -1 -1 -1
Ezetimibe 10mg 622 -12 -18 -15 -7 +1

Study 2 Placebo 226 +1 +1 -1 +2 -2
Ezetimibe 10mg 666 -12 -18 -16 -9 +1

Pooled data' Placebo 431 0 +1 -2 0 -2
Ezetimibe 10mg 1288 -13 -18 -16 -8 +1
N=number of subjects, Total-C total cholesterol, LDL low density lipoproteins, Apo B=apolipoprotein B, TGtriglycerides, HDL high density lipoproteins
"median % change from baseline; baseline (on no lipid-lowering drug), CEzetimibe significantly reduced Total-C, LDL, Apo B, and TG, and increased HDL
compared to placebo.


has no effect on the extent of absorption of
ezetimibe. However, co-administration with a high-
fat meal increases the Cmax of ezetimibe by 38%.5
The absolute bioavailability cannot be determined
since ezetimibe is insoluble in aqueous media suit-
able for injection. Ezetimibe and its active metabo-
lite are highly bound to human plasma proteins
(90%).5
Ezetimibe is primarily metabolized in the
liver and the small intestine via glucuronide conju-
gation with subsequent renal and biliary excretion.
Both the parent compound and its active metabolite
are eliminated from plasma with a half-life of ap-
proximately 22 hours allowing for once daily dos-
ing. Ezetimibe lacks significant inhibitor or inducer
effects on cytochrome P-450 isoenzymes which ex-
plains its limited number of drug interactions
(Table 4). No dose adjustment is needed in patients
with renal insufficiency or mild hepatic dysfunction
(Child-Pugh score 5-6). Due to insufficient data, the
manufacturer does not recommend ezetimibe for
patients with moderate to severe hepatic impair-
ment (Child-Pugh score 7-15). In patients with


mild, moderate, or severe hepatic impairment, the
mean AUC values for total ezetimibe are increased
approximately 1.7-fold, 3-4 fold, and 5-6 fold re-
spectively, compared to healthy subjects.5

Clinical Trials

Ezetimibe Monotherapy
In two multicenter, double blinded, placebo-
controlled 12 week studies that compared ezetimibe
monotherapy with placebo in 1719 patients with
primary hypercholesterolemia, ezetimibe signifi-
cantly lowered total-C, LDL, Apo B, and TG, and
increased HDL compared to placebo (Table 1).5

Add-on to Statin
In a multicenter, double-blinded, placebo-
controlled 8 week study, 769 patients with primary
hypercholesterolemia, CHD, or multiple cardiovas-
cular risk factors who were receiving a station but
had not met their NCEP ATP III LDL goal were
randomized to receive either ezetimibe or placebo
in addition to their on-going station therapy.
Ezetimibe, added to on-going station therapy, sig-


Table 2. Response to the addition of ezetimibe to on-going station therapy in patients with hypercholesterolemia after 8
weeks meanb % change from treated baselinec6

Treatment (Daily Dose) N Total-C LDL Apo B TG HDL

On-going station + Placebod 390 -2 -4 -3 -3 +1

On-going station + Ezetimibe 10mgd 379 -17 -25 -19 -14 +3


N=number of subjects, Total-C total cholesterol, LDL low density lipoproteins, Apo B=apolipoprotein B, TGtriglycerides, HDL high density lipoproteins
patients receiving each station: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin, fluvastatin, cerivastatin, lovastatin); median % change from baseline;
Baseline (on a station alone); dezetimibe 10mg + station significantly reduced Total-C, LDL, Apo B, and TG, and increased HDL compared to station alone.

Iharm Nolnt \/nlllim 1Q Icc"ii 7 Anril O2nnQ


P


I I I I I I IDI i


.lu Illl i Igtu ^ [ / ill Vp /,







Table 3. Response to ezetimibe and simvastatin initiated at the same time in patients with primary hypercholesterolemia
meana % change from untreated baselineb7

Treatment (Daily Dose) N Total-C LDL Apo B TGa HDL

Placebo 70 -1 -1 0 +2 +1
Ezetimibe 61 -13 -19 -14 -11 +5
Simvastatin 10mg 70 -18 -27 -21 -14 +8
Ezetimibe + Simvastatin 10mg 67 -32 -46 -35 -26 +9
Simvastatin 20mg 61 -26 -36 -29 -18 +6
Ezetimibe + Simvastatin 20mg 69 -33 -46 -36 -25 +9
Simvastatin 40mg 65 -27 -38 -32 -24 +6
Ezetimibe + Simvastatin 40mg 73 -40 -56 -45 -32 +11
Simvastatin 80mg 67 -32 -45 -37 -23 +8
Ezetimibe + Simvastatin 80mg 65 -41 -58 -47 -31 +8
Pooled Data (Simvastatin) 263 -26 -36 -30 -20 +7
Pooled Data (Ezetrimibe + Simvastatin)c 274 -37 -51 -41 -29 +9

N=number of subjects, Total-C total cholesterol, LDL low density lipoproteins, Apo B apolipoprotein B, TG-triglycerides, HDL high density lipoproteins
"median % change from baseline, baseline (on no lipid-lowering drug), cEzetimibe 10mg + all doses of simvastatin pooled (10-80mg) significantly reduced
Total-C, LDL, Apo B, and TG, and increased HDL compared to all doses of simvastatin pooled (10-80mg).


nificantly lowered total-C, LDL, Apo B, and TG,
and increased HDL compared with the station ad-
ministered alone (Table 2).6 In addition, the investi-
gators concluded that LDL reductions with
ezetimibe were generally consistent across all stat-
ins.
Coadministration i i/h Statin
In a multicenter, double-blinded, placebo-
controlled 12 week trial in 668 hypercholes-
terolemic patients, ezetimibe 10mg alone or pla-
cebo was initiated at the same time with simvas-
tatin 10mg-80mg. Ezetimibe significantly lowered
total-C, LDL, Apo B, and TG, and increased HDL
compared with simvastatin administered alone
(Table 3).7 In three other similar multicenter, dou-
ble blinded, placebo-controlled 12 week trials in
hypercholesterolemic patients that compared the
benefits of ezetimibe initiated concurrently with
atorvastatin, pravastatin, and lovastatin, ezetimibe
significantly lowered total-C, LDL, Apo B, and
TG, and with the exception of pravastatin increased
HDL compared to the station administered alone.5
In a double-blinded, randomized, 12 week
study, 50 patients with homozygous familial hy-
percholesterolemia already receiving atorvastatin or


simvastatin were randomized to one of three treat-
ment groups; atorvastatin or simvastatin (80mg),
ezetimibe administered with atorvastatin or sim-
vastatin (40mg), or ezetimibe administered with
atorvastatin or simvastatin (80mg). Ezetimibe ad-
ministered with atorvastatin or simvastatin (40 and
80mg pooled stations groups), significantly reduced
LDL (20.7%) compared with increasing the dose of
atorvastatin or simvastatin monotherapy from 40 to
80mg (7%).8 In the subgroup of patients who where
treated with ezetimibe plus 80mg atorvastatin or
simvastatin, LDL was reduced by 27.5%.8

Adverse Effects
Ezetimibe's safety has been evaluated in
more than 4700 patients.5 Clinical studies have
demonstrated that ezetimibe is generally well toler-
ated when administered alone or in combination
with a station 5 When compared to placebo, the over-
all incidence of adverse effects was similar. Like-
wise, the discontinuation rate due to adverse effects
was similar to placebo.5 In general, adverse effects
were similar between ezetimibe administered with
stations and stations alone. However, the frequency of
increased transaminases was slightly higher in pa-
tients receiving ezetimibe in combination with stat-


Pha rma Note Volume 18, Issue 7 April 2003


PharmaNote


Volume 18, Issue 7 April 2003







Table 4. Potential Drug-Drug Interactions with ezetimibe5'9
Drug


Antacids


Cholestyramine



Colesevelam
Colestipol
Cyclosporine

Fibrates


Fenofibrate
Gemfibrozil


Administering ezetimibe with antacids has no significant effect on the AUC of ezetimibe or its active metabo-
lite. However, the peak plasma concentration of ezetimibe is decreased by 30%. To minimize this interaction,
it is recommended that ezetimibe be administered 2 hrs before or 4 hrs after the administration of antacids.
Mean AUC of ezetimibe was decreased approximately 55% when it was administered concomitantly with
cholestyramine. To minimize this interaction, ezetimibe should be administered 2 hrs before or 4 hrs after the
administration of cholestyramine. A similar effect might be expected to occur with the concomitant admini-
stration of colestipol or colesevelam with ezetimibe; however, this potential interaction has not been studied.
Similar effect as cholestyramine is expected; however, this potential interaction has not been studied.
Similar effect as cholestyramine is expected; however, this potential interaction has not been studied.
Ezetimibe levels were increased 12 fold in one renal transplant patient receiving multiple medications includ-
ing cyclosporine.
Fibrates can increase cholesterol excretion into the bile which in turn has the potential to promote cholelithi-
asis. In pre-clinical trials, ezetimibe was reported to increase cholesterol in gallbladder bile in dogs. Theoreti-
cally this would increase the risk of having cholelithiasis; therefore, the manufacturer does not recommend the
use of ezetimibe in patients receiving fibrates.
Concomitant administration with ezetimibe resulted in 1.5 fold increase in total ezetimibe concentrations.
Concomitant administration with ezetimibe resulted in 1.7 fold increase in total ezetimibe concentrations.


*This list is not all inclusive as it is based on findings in pre-clinical trials. More drug-drug interactions may evolve as ezetimibe is used in clinical practice.


ins than in patients receiving stations alone.5 Due to
this unexplained transient increase in liver en-
zymes, the manufacturer does not recommend the
use of ezetimibe in patients with moderate or se-
vere hepatic dysfunction. When used in patients
with mild hepatic dysfunction, close monitoring is
recommended.

Drug Interactions
Ezetimibe lacks significant inhibitor or in-
ducer effects on cytochrome P-450 isoenzymes. Po-
tential drug-drug interactions are listed in Table 4.

Cost
The cost of a 30-day supply of Zetia 10mg
ranges from $50-60 per month.9

Summary
Ezetimibe, used alone or in combination
with stations, positively affects the lipid profile of
patients with hypercholesterolemia by primarily de-
creasing LDL cholesterol. Ezetimibe's tolerability
and effectiveness has been demonstrated in multi-
ple clinical trials. Co-administration of ezetimibe
with stations offers a new approach to further reduce
LDL cholesterol while avoiding high doses of stat-
ins, thus allowing more patients to reach their treat-
ment goals in a safe and effective manner.


References
1. American Heart Association. 2001 Heart and Stroke Sta-
tistical Update. Dallas, Texas: American Heart Associa-
tion; 2000.
2. Executive summary of the third report of the national
cholesterol education program (NCEP) expert panel on
detection, evaluation, and treatment of high blood choles-
terol in adults (adult treatment panel III). JAMA
2001;285:2486-2497.
3. Van Heek M, France CF, Compton DS, et al. In vivo me-
tabolism-based discovery of a potent cholesterol absorp-
tion inhibitor, SCH58235, in the rat and rhesus monkey
through the identification of the active metabolites of
SCH48461. J Pharmacol Exp Ther 1997;283: 157-163.
4. Knopp RH, Bays H, Manion CV, et al. Effect of
ezetimibe on serum concentrations of lipid-soluble vita-
mins (abstract) Atherosclerosis 2001;2 (suppl):90.
5. Zetia Product Information. Merck/Schering-Plough
Pharmaceuticals, 2002.
6. Gagne C, Bays HE, Stuart R, et al. Efficacy and safety of
ezetimibe added to ongoing station therapy for treatment
of patients with primary hypercholesterolemia. Am J Car-
diol 2002;90:1084-1091.
7. Davidson MH, et al. Ezetimibe coadministered with sim-
vastatin in patients with primary hypercholesterolemia. J
Am Coll Cardiol 2002;40:2125-2134.
8. Gagne C, Gaudet D, Bruckert E, et al. Efficacy and safety
of ezetimibe coadministered with atorvastatin or simvas-
tatin in patients with homozygous familial hypercholes-
terolemia. Circulation 2002;105:2469-2475.
9. Zetia Drug Monograph. Clinical Pharmacology Online
2003 January. Gold Standard Media. Available from:
URL: http://cpip.gsm.com.


m
Pha rma Note Volume 18, Issue 7 April 2003


Effect


PharmaNote


Volume 18, Issue 7 April 2003







DUTASTERIDE (AVODART"):
A NEW 5a-REDUCTASE
INHIBITOR


Vivian Sebako, Pharm. D. Candidate


Introduction
Benign Prostatic Hypertrophy (BPH) is the
most common cause of voiding dysfunction in
men. The disorder affects men over the age of 45
and increases in frequency with age so that by the
eighth decade of life more than 90% of men have
prostatic hypertrophy at autopsy.1'2 BPH is a het-
erogeneous disease, which may be asymptomatic
but often becomes symptomatic from the fifth dec-
ade of life. Obstructive symptoms of the disease
include weak urinary stream/dribbling, urinary
hesitancy and sensation of incomplete voiding; irri-
tative symptoms include urinary frequency, ur-
gency and nocturia. Medical and/or surgical treat-
ment is indicated when symptoms interfere with
quality of life.3
The development of BPH requires a combi-
nation of testicular androgens and the ageing proc-
ess. Although the role of androgens as a causative
factor for BPH is debated, they undoubtedly play,
at least, a permissive role.4 Dihydrotestosterone
(DHT) is the primary androgen responsible for
prostatic enlargement and bladder outlet obstruc-
tion, and contributes to the progressive nature of
the disease. It is generated by the reduction of tes-
tosterone, a process that utilizes two isoenzymes of
5a-reductase. Although not elevated in BPH, DHT
levels in the prostate remain at normal levels de-
spite decreasing levels of testosterone that occur
with age.
Several forms of medical or surgical treat-
ments are available for men with advanced symp-
toms. Treatment with luteinizing hormone-
releasing hormone (LHRH) analogues or 5a-
reductase inhibitors shrinks prostatic hyperplastic
cells by lowering tissue DHT levels.
Dutasteride, which is manufactured by
GlaxoSmithKline, is the newest addition to the 5a-
reductase class. It was approved by the FDA on
November 20, 2001 for the treatment of lower uri-


nary tract symptoms (LUTS) due to enlarged pros-
tate and BPH.
This article will review pertinent pharma-
cology, pharmacokinetics, clinical trials, adverse
drug reactions, drug interactions, dosage, and eco-
nomic issues related to dutasteride.

Pharmacology/Pharmacokinetics
Durasteride is a competitive and specific
inhibitor of both type 1 and type 2 Sa-reductase
isoenzymes. Both isoenzymes are involved in the
conversion of testosterone to 5u-DHT, the primary
androgen that stimulates the development and sub-
sequent enlargement of the prostate gland. Type 2
isoenzyme is primarily active in the reproductive
organs (prostate, seminal vesicles, epididymides)
and is responsible for two-thirds of circulating
DHT. Type 1 isoenzyme is mostly active in the
liver and the skin. Compared to finasteride, which
inhibits mostly the type 2-isoenzyme, dutasteride
inhibits type 1 isoform as well, reducing DHT for-
mation in the skin and liver. Studies with finas-
teride have shown that the drug reduces circulating
levels of DHT by 60-80% from baseline while du-
tasteride reduced the levels by more than 90%5,6
This higher potency is due to dual inhibition of
5a -reductase enzymes. In addition dutasteride re-
duced the mean prostate volume by a mean of
25.7% at 24 months and BPH related surgical inter-
vention by 48% compared to placebo.
Following oral administration of a single
0.5 mg dose, the time to peak serum concentration
(Tmax) occurred within 2-3 hours.' The absolute oral
bioavailability in healthy subjects is approximately
60% (range 40%-90%). When the drug is adminis-
tered with food, the maximum serum concentra-
tions were reduced by 10%-15%, however this re-
duction is of no clinical significance. Dutasteride is
highly bound (99%) to plasma albumin and alpha-1
glycoprotein. Pharmacokinetic data shows that the
drug has a large volume of distribution (300-500L).
Similar to plasma, steady state concentrations in
semen were achieved six months after continuous
administration of the drug.
Dutasteride is extensively metabolized by
the CYP3A4 isoenzyme to three major and two mi-
nor metabolites. Only one of the major metabolites,
6p-hydroxydutasteride has pharmacological activ-
ity comparable to that of the parent drug. The drug


Pha rma Note Volume 18, Issue 7 April 2003


PharmaNote


Volume 18, Issue 7 April 2003







Table 1. Changes in primary and secondary endpoints: placebo vs. dutasteride6
Parameter Time Placebo Dutasteride Group Comparison
(units) (months) (mean SD) (mean SD) (p-value)

Serum DHT (pg/ml) 24 16 150 -389 228 <0.001
Serum Testosterone (pg/ml) 24 36 1226 749 1475 <0.001
TPV (cm3) 24 0.8 14.3 -14.6 13.5 <0.001
AUA-SI 24 -2.3 6.8 -4.4 6.6 <0.001
Qmx (ml/s) 24 0.6 4.7 2.2 5.2 <0.001
Serum PSA (ng/ml) 24 0.5 2.1 -2.2 2.0 <0.001
DHT dihydrotestosterone, TPV total prostate volume, Qm =maximal flow rate, AUA-SI=American Urological AssociationSymptom Index, PSA prostate
specific antigen.


and its metabolites were excreted mainly in the fe-
ces, with 5% as unchanged drug and 40% metabo-
lites. The terminal elimination half-life at steady
state is approximately 5 weeks, and serum concen-
trations of the drug remain detectable for 4-6
months after treatment is stopped.8 It is believed
that the increased DHT lowering effect of du-
tasteride is not only due to its greater inherent po-
tency, but also its long terminal half-life.9

Clinical Trials
A limited number of trials are available
which evaluate the efficacy, safety and tolerability
of dutasteride. To date, the safety and efficacy of
the drug has been reported on the basis of three
pooled 2-year Phase III clinical trials.
GG Roehrborn et al. summarized and pre-
sented the data from the three trials. A total of 4325
men aged 50 years and over with clinical benign
prostatic hyperplasia and moderate to severe symp-
toms were enrolled in three identical trials and ran-
domized to dutasteride 0.5 mg or matching placebo.
After 1 month of a single-blind placebo-run-in pe-
riod, patients were followed for 24 months in a
double-blinded fashion with assessments done at
multiple intervals. The primary endpoints were
changes in American Urological Association-
Symptom Index (AUA-SI) and risk of Acute Uri-
nary Retention (AUR). Secondary endpoints in-
cluded: changes in total prostate volume (TPV),
maximal flow rate (Qmax), surgical intervention, se-
rum prostate specific antigen (PSA), serum testos-
terone, serum DHT, and safety and tolerability of
the drugs. In all the studies, the assessment was
done at 1, 3, 6, 12, 18, and 24 months for AUA-SI,


Qmax, and PSA and at 12 and 24 months for testos-
terone and DHT. The TPV was measured at 1, 3, 6,
12, and 24 months. Out of the 4325 men who were
randomized, 2951 men (68%) completed the 24-
month follow-up period. The dropout rate for the
dutasteride group and placebo was 30.32% and
33.32% respectively. Reasons for discontinuation
included lack of efficacy (25.18%), adverse event
(28.02%), loss of follow-up (8.66%) and consent
withdrawal (19.21%). However, the only reason
for discontinuation that reached statistical signifi-
cance between the dutasteride and placebo-treated
groups was lack of efficacy, 20.39% versus 29.57%
(p< 0.001).
The pooled results from these studies
showed that serum DHT changed by a mean of
+9.6% versus -90.2% at 24 months in the placebo
and dutasteride groups respectively. Fifty-eight per-
cent of dutasteride-treated patients achieved a 90%
or greater reduction at 1 month and 85% of patients
achieved 90% or greater reduction at 12 months.
Serum testosterone changed by +5.4% versus
+24.5% in the placebo and dutasteride groups at 24
months respectively. The TPV decreased signifi-
cantly in dutasteride-treated patients starting at 1
month and continuing throughout the 24 months of
the study (p<0.001). Clinical significant differences
between the placebo and dutasteride-treated pa-
tients were also observed for AUA-SI scores. The
changes from baseline were demonstrated as early
as 3 months but reached significance at 6 months.
Continued improvement was noted at 12, 18, and
24 months compared with the placebo. The maxi-
mal flow rate increased by 0.6 ml/second in the pla-
cebo group and 12.2 ml/second in the dutasteride


Pha rma Note Volume 18, Issue 7 April 2003


PharmaNote


Volume 18, Issue 7 April 2003







Table 2. Adverse events associated with dutasteride use (24 month study period)6'7
Placebo Dutasteride Comparison between groups
Adverse Events
(N=2158) (N=2167) (p-value)
Impotence 4.0% 7.3% < 0.001
Decreased libido 2.1% 4.2% <0.001
Gynecomastia 0.7% 2.3% < 0.001
Ejaculation disorder 0.8% 2.2% < 0.001


group at 24 months. The change from baseline was
significant, as was the difference between du-
tasteride and placebo at 1 month on all measured
endpoints. At 24 months serum PSA levels in-
creased 15.8% from baseline in the placebo group
compared to a 52.4% decrease in the dutasteride
group. The incidence of AUR was 4.2% in the pla-
cebo-treated group compared to 1.8% in du-
tasteride-treated patients. The relative risk of AUR
with the drug compared to placebo was 0.43 and
the risk reduction was 57% (p<0.001).
The results of these studies indicate that,
compared to placebo, dutasteride exhibits clinically
significant effects in terms of DHT reduction, re-
duction of prostate volume and symptoms, flow
rate improvement, and reduction of the risk of
AUR and surgery over a 24-month period. In addi-
tion, the drug was well tolerated with a side effect
profile that compared favorably with existing 5a-
reductase inhibitors1 (Tablel summarizes these re-
sults).

Dosage and Administration
Dutasteride is available as a 0.5 mg gelatin
capsule. The recommended dose is a single capsule
taken orally once a day. It should be swallowed
whole and may be taken with or without food. No
dosage adjustment is necessary for subjects with
renal impairment or for the elderly. The effect of
hepatic impairment on the pharmacokinetics of du-
tasteride has not been studied. Because the drug is
extensively metabolized in the liver, exposure
could be higher in hepatically impaired patients.'

Adverse Effects
Dutasteride was well tolerated in clinical
trials. Overall, 75% of placebo treated patients and
77% of dutasteride-treated patients experienced an
adverse event in the course of the 24-month study.


The most common adverse events were muscu-
loskeletal pain, upper respiratory tract infections,
and ear, nose, and throat infections, Adverse
events related to the drug were seen in 14% and
19% of placebo-treated and dutasteride-treated pa-
tients respectively. The most common drug-related
adverse events were impotence, decreased libido,
ejaculation disorders, and gynecomastia. Over the
two-year treatment period, 9% of patients in the
placebo and drug treatment arms withdrew from the
study due to adverse events. Similar to finasteride,
dutasteride may inhibit the development of the ex-
ternal genitalia of the male fetus; therefore, preg-
nant women should not handle the drug as it can be
absorbed through the skin. Dutasteride may inter-
fere with prostate cancer screening because it de-
creases serum concentrations of prostate specific
antigen (PSA) by about 50%. Table 2 summarizes
the adverse events associated with the use of du-
tasteride.

Drug Interactions
In vitro drug metabolism studies reveal that
dutasteride is metabolized by human cytochrome
isoenzyme CYP3A4.7 In human studies the drug
was found to be extensively metabolized with only
less than 20% of the drug being excreted un-
changed in feces. To date no clinical drug interac-
tion studies have been done to evaluate the effects
of CYP3A4 inhibitors on the pharmacokinetics of
dutasteride. However, based on the in vitro data,
blood concentrations of dutasteride may increase in
the presence of inhibitors of CYP3A4 such as ri-
tonavir, ketoconazole, verapamil, diltiazem, ci-
metidine and ciprofloxacin.7 Clinical drug interac-
tion studies have shown no pharmacokinetic or
pharmacodynamic interactions between dutasteride
and tamsulosin, terazosin, warfarin, digoxin and
cholestyramine.


Ph ra ot Vlue 8,Isue7 prl 00


PharmaNote


Volume 18, Issue 7 April 2003








Cost
Based on three local community pharma-
cies, the mean retail price for a 30-day supply of
dutasteride was $87.96. The price ranged from
$84.74 to $97.19.

Summary
Dutasteride is the second 5a-reductase in-
hibitor approved by the FDA for the treatment of
symptoms associated with BPH. The drug is a po-
tent, competitive, and irreversible inhibitor of the
two isoenzymes that convert testosterone to DHT.
Dutasteride 0.5mg/day has been found to be safe
and effective, reducing circulating DHT levels by
85% at week 1 and by 90% after 2 weeks of initiat-
ing treatment. Dutasteride represents an additional
therapeutic option in the treatment of BPH; how-
ever, further studies are needed to determine if the
drug offers any clinically significant advantages
over finasteride.

References
1. Jonler M, Riehmann M, Bruskewitz R. Benign Prostatic
Hyperplasia: Current Pharmacological Treatment. Drugs.
1994 Jan; 47(1): 66-81.
2. Isselbacher KJ, Braunwald E et al. Harrison's Principles
of Internal Medicine. 13' edition, 1994. McGraw-Hill
Inc. pp 1862-65.
3. Dull P, Reagan R, Bahnson R. Managing Benign
Prostatic Hyperplasia. American Family Physician. 2002;
66(1): 77-83.
4. Bartsch G, Rittmaster RS, Klocker H. Dihydrotestoster-
one and the concept of 5alpha-reductase in human benign
prostatic hyperplasia. World J Urology. 2002 Apr; 19(6):
413-25.
5. Vermeulen A, Giagulli VA et al. Hormonal effects of an
orally active 4-azasteroid inhibitor of 5a-reductase in hu-
mans. Prostate 1989; 14:45-53.
6. Roehrborn CG, Boyle P et al. Efficacy and safety of a
dual inhibitor of 5-alpha-reductase types and 2
(Dutasteride) in men with benign prostatic hyperplasia.
Urology. 2002 Sep; 60(3): 434:41. Dutasteride Package
Insert, 2001.
7. Gislosko PO et al. Clinical pharmacokinetics and phar-
macodynamics of Dutasteride. British J Clinical Pharma-
cology. 1999; 47:53.
8. Bramson HN, Hermann D et al. Unique preclinical char-
acteristics of CG745, a potent inhibitor of 5AR. J Pharm
Exp Ther 1997; 282:1496-502.
9. McConnell JD, Bruskewitz R et al. Effect of finasteride
on the risk of acute urinary retention and need for surgi-
cal treatment among men with benign prostatic hyperpla-
sia. NEJM. 1998; 338:557-63.


Alinia (nitazoxanide) is a new antiprotozoal
agent used for the treatment of diarrhea
caused by Cryptosporidium parvum and
Giardia lamblia in pediatric patients 1
through 11 years of age. The usual dosage
for children 12 to 47 months old is 5mL
ql2h for 3 days and for children 4 to 11
years old 10mL ql2h for 3 days. This
medication should be taken with food.









Relpax (eletriptan hydrobromide) is a new
5-HT1B,1D receptor antagonist for the acute
treatment of migraine attacks with or without
aura. The usual dosage for adults is 20mg or
40mg at onset of headache. If it recurs after
initial relief, may repeat after 2 hours. The
maximum daily dose is 80mg. Avoid use in
patients with severe hepatic impairment.







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
Pharm.D.

R. Whit Curry, M.D. Associate Editor

John M. Tovar Assistant Editor
Pharm.D.


Pha rma Note Volume 18, Issue 7 April 2003


PharmaNote


Volume 18, Issue 7 April 2003




University of Florida Home Page
© 2004 - 2010 University of Florida George A. Smathers Libraries.
All rights reserved.

Acceptable Use, Copyright, and Disclaimer Statement
Last updated October 10, 2010 - - mvs