Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00011
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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: May 2003
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Lili Olga Duthiers, Pharm.D. Candidate

Abilify (aripiprazole) is a quinolinone
derivate, and the first of a new class of atypical an-
tipsychotics. Its FDA approved indications in-
clude: acute, relapsing, and stable chronic schizo-
phrenia. The drug was jointly developed by Bris-
tol-Myers Squibb Company and Otsuka America
Pharmaceutical, Inc. Aripiprazole was approved
on Nov 15, 2002, and marketed around two weeks
thereafter. It has demonstrated efficacy in clinical
trials in patients with acute relapse or stable chronic
schizophrenia, improving symptoms at least as ef-
fectively as haloperidol and to a similar extent as
risperidone. Treatment with aripiprazole shows im-
provements in both positive and negative symp-
toms of schizophrenia. This article will focus on
the pharmacology/pharmacokinetics, dosing, clini-
cal trials, and safety profile of aripiprazole.

Aripiprazole is a partial agonist at dopamine
D2and serotonin 5-HT1Areceptors, and an antago-
nist at 5-HT2A receptors. It is best described as a
dopamine-serotonin system stabilizer. Aripipra-
zole's activity is due to the parent drug, and to a
lesser extent, to its major metabolite, dehydro-
aripiprazole. Dehydro-aripiprazole has affinity for
D2 receptors similar to the parent drug. It repre-
sents about 40% of the parent drug exposure in
plasma. The mean elimination half-life is 75 hours

and 94 hours for aripiprazole and dehydro-
aripiprazole, respectively. At steady state, the phar-
macokinetics are dose-proportional. There is some
orthostatic hypotension observed with aripiprazole,
which may be explained by its antagonist activity at
adrenergic alpha receptors.
Aripiprazole is well absorbed with peak
plasma concentration occurring within 3-5 hours of
administration. Absolute oral bioavailability of the
tablet formulation is 87%. Aripiprazole can be
given without regard to food. At steady state, fol-
lowing IV administration of the drug, the volume of
distribution is 404 L or 4.9 L/kg. At therapeutic
concentrations aripiprazole and its major metabolite
are greater than 90% bound to serum proteins,
mainly albumin. Pharmacokinetics of a single dose
of aripiprazole 15 mg were not significantly altered
by age or hepatic impairment (Child-Pugh class A
to C).9 The maximum plasma concentration (Cmax)
and area under the curve (AUC) of aripiprazole and
its active metabolite are 30 to 40% higher in
women than in men. The corresponding oral clear-
ance of the drug is lower in women. These differ-
ences are explained by women's lower bodyweight
compared to men. No dosage adjustment is neces-
sary based on gender. Studies in human volunteers
suggest that the pharmacokinetics of aripiprazole
are dose proportional between dosages of 5 and 30
mg. In a study in which volunteers received titrated
doses of aripiprazole 10 mg/day for 2 days, 20 mg/
day for 2 days, and 30 mg/day for 10 days, Cmaxon
day 14 was 452 mcg/L and Tmaxwas 3 hours.9 Half-
life was 60 hours. Healthy human volunteers were
given 0.15 mg to 30 mg/day of aripiprazole for 14
days, resulting in a dose-dependent D2 receptor oc-
cupancy, indicating brain penetration of aripipra-
zole in humans.10 When aripiprazole 30 mg/day
was co-administered with therapeutic dosages of

Pha rma Note Volume 18, Issue 8 May 2003




Volume 18, Issue 8 May 2003

lithium or valproic acid for 22 days, it produced no
clinically significant changes in the pharmacokinet-
ics of aripiprazole or the metabolite at steady state
in healthy volunteers.5 This was despite a 15-20%
increase in aripiprazole Cmax and AUC during lith-
ium administration, and 25% decreases in these pa-
rameters with concurrent administration of valproic
Aripiprazole is metabolized by three main
pathways: dehydrogenation, hydroxylation, and N-
dealkylation. Based on information gathered from
in vitro studies, CYP3A4 and CYP2D6 are en-
zymes responsible for dehydrogenation and hy-
droxylation of aripiprazole, and N-dealkylation is
catalyzed by CYP3A4. Aripiprazole is the pre-
dominant drug moiety in the systemic circulation.

Clinical Trials

\l n, t-Term Trials
The efficacy of aripiprazole in patients with
schizophrenia has been compared with that of
haloperidol or risperidone in two randomized, 4-
week, placebo-controlled trials and assessed in sev-
eral dose-ranging studies. Additional trials include
two randomized, double-blind long-term trials com-
paring aripiprazole with placebo or haloperidol, a
trial in which patients were switched to aripiprazole
monotherapy, a meta analysis of double blind,
fixed-dose placebo-controlled trials, and an exami-
nation of the neurocognitive effects of the drug ver-
sus those of olanzapine. Primary endpoints were
changes in scores for the Positive and Negative
Symptom Scale (PANSS) as well as the Clinical
Global Impressions Severity of Illness (CGI-S) and
Global Improvement (CGI-I) scales. Other end-
points included changes in the Brief Psychiatric
Rating Scale (BPRS), Montgomery-Asberg Depres-
sion Rating Scale (MADRS), mean CGI score, and
responder rates (CGI-I score of 1 or 2 or a = 30%
decrease in PANSS total score).
Two 4-week randomized, double-blind mul-
ticentre, placebo-controlled trials compared aripip-
razole with either haloperidol or risperidone ther-
apy in hospitalized patients with acute relapse of
schizophrenia or schizo-affective disorder, who had
previously responded to antipsychotic therapy.2,14
Baseline PANSS score ranged from 92-100. After
a 3-5 day washout period, patients received either
placebo or active treatment. Both aripiprazole (15

mg or 30 mg/day; n=102 in both groups) and halop-
eridol (10 mg/day; n=104) significantly reduced
scores for PANSS total and positive, CGI-I, CGI-S
and BPRS (last observation carried forward analy-
sis: p=0.002 vs. placebo).2 Aripiprazole 15 mg/day
(p<0.006) and haloperidol (p<0.05), but not aripip-
razole 30 mg/day, also significantly improved
PANSS negative score compared with placebo. In
contrast, the response rate with either dosage of
aripiprazole (35 and 28% respectively, p<0.05), but
not haloperidol (26%) was greater than with pla-
cebo (17%). Likewise, PANSS total, positive and
negative scores and those for CGI-I and CGI-S
were significantly decreased with aripiprazole 20 or
30 mg/day (n=101; p=0.05 vs. placebo) and risperi-
done 3 mg twice daily (n=99; p=0.05 vs. pla-
cebo).14 In addition, negative parameters improved
at week 1 with aripiprazole, which was earlier than
with risperidone.

Long-Term Trials
In a 26-week trial of 310 patients with sta-
ble, chronic schizophrenia, aripiprazole 15 mg/day
increased the time to relapse (primary endpoint) 2-
fold (p<0.001), produced fewer relapses (34 vs.
57%, p<0.001), and from week 6 of therapy im-
proved PANSS total and positive scores greater
than placebo (p=0.05).1 Likewise, in a prospective,
combined analysis of a US and European trial,
more patients with acute relapse of chronic schizo-
phrenia treated with aripiprazole 30 mg/day
(n=853) than haloperidol 10 mg/day (n=430) re-
sponded to and continued with treatment at weeks
8, 26, and 52 (p=0.012). Response rate (defined as
a 30% decrease in PANSS total score maintained
for at least 28 days) at 52 weeks was 52% versus
44% (p=0.003) for aripiprazole and haloperidol re-
spectively. Aripiprazole therapy was also superior
to haloperidol on the PANSS negative subscale at
weeks 26 and 52, and on the MADRS total score
(assessing depressive symptoms) at weeks 8, 26
and 52 (p<0.05 for all). However, there were no
differences between the two groups in the primary
endpoints (response defined as a 20% decrease in
PANSS total score at any time, and time to failure
to maintain response) or in PANSS total score.7

Dose-Ranging or Switch Trials
In a double-blind, placebo-controlled trial
by Daniel et al.,6 307 patients with acute relapse of

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Volume 18, Issue 8 May 2003

Table 1. Percentage of patients reporting adverse events in short-term placebo-controlled trials
Aripiprazole Placebo
Body System Adverse Event (n=926) (n=413)

Body as a whole Headache 32% 25%
Asthenia 7% 5%
Fever 2% 1%
Digestive System Nausea 14% 10%
Vomiting 12% 7%
Constipation 10% 8%
Nervous System Anxiety 25% 24%
Insomnia 24% 19%
Lightheadedness 11% 7%
Somnolence 11% 8%
Akathisia 10% 7%
Tremor 3% 2%
Respiratory System Rhinitis 4% 3%
Coughing 3% 2%
Skin and Appendages Rash 6% 5%
Special Senses Blurred vision 3% 1%

schizophrenia received either aripiprazole 2, 10 or
30 mg/day or haloperidol 10 mg/day for 4 weeks.
Aripiprazole 30 mg/day significantly decreased
scores for CGI-S, BPRS total, BPRS core, PANSS
total and PANSS positive and negative subscales
compared with placebo (p-value not given). Effi-
cacy was apparent at week 1 and was sustained
throughout the study. On the other hand, aripipra-
zole 2 or 10 mg/day showed significant reductions
only in BPRS total and PANSS total score.6
In a separate pooled report of two 4-week
double-blind, placebo-controlled studies of 410 pa-
tients with acutely relapsing schizophrenia, which
included the trial by Daniel et al. and another by
Petrie15, aripiprazole 30 mg/day was more effica-
cious than either 2 or 10 mg/day, and showed an
early onset of efficacy (apparent on all variables at
week 1). In the study by Petrie15, the aripiprazole
dosage was titrated from 5 to 30 mg/day over 13
days and aripiprazole (2 to 30 mg/day) showed
greater clinical efficacy than placebo, improving
scores for BPRS (total and core), CGI-S and
PANSS total.
Three-hundred and eleven patients with sta-

ble, chronic disease were randomized to aripipra-
zole 30 mg/day with abrupt discontinuation of the
current antipsychotic or with 2-week tapering of the
current medication, or aripiprazole 10 to 30 mg/day
titrated over 2 weeks with simultaneous tapering of
the current medication. Efficacy was maintained or
improved after switching to aripiprazole monother-
apy from current antipsychotics haloperidoll, thiori-
dazine, risperidone, or olanzapine); whereas,
PANSS total score decreased regardless of previous

Meta Analysis
A meta analysis was performed on data
from 1545 hospitalized patients with acute relapse
enrolled in four 4- to 6-week randomized, multi-
center, double-blind, fixed-dose, placebo-controlled
trials (this included the 4-week comparisons be-
tween haloperidol and risperidone). Aripiprazole in
dosages = 15 mg/day was superior to placebo at
week 1 and throughout treatment.8
Neurocognitive function improved more
with aripiprazole than with olanzapine in outpa-
tients with stable schizophrenia. At 8 and 26

Pha rma Note Volume 18, Issue 8 May 2003


Volume 18, Issue 8 May 2003

weeks, verbal learning increased to a greater extent
in the group given aripiprazole 30 mg/day (n=76)
than in olanzapine 15 mg/day recipients (n=93)
(p<0.04). Both drugs improved working memory
as compared with baseline at week 8 (p<0.05) and
tended to do so at week 26. Neither drug had any
effect on problem solving.4

Adverse Effects

Most Common Adverse Events
In the 4-week trial that compared aripipra-
zole versus haloperidol and placebo, headache,
anxiety, insomnia, nausea, and dizziness were the
most commonly reported adverse events at doses of
15 and 30 mg/day. Akathisia and somnolence were
3 times more frequent with haloperidol than with
aripiprazole, whereas nausea and dizziness were
experienced twice as often with aripiprazole. The
only adverse event to have an apparent dose-
response relationship was somnolence and was
most common at a 30 mg/day dose.

Extrapyramidal Symptoms
In the 4-week trials, the incidence of ex-
trapyramidal symptoms (EPS) was similar in pa-
tients treated with aripiprazole 15-30 mg/day,
risperidone 3 mg twice daily and placebo. How-
ever, it was higher in patients treated with haloperi-
dol compared to aripiprazole and placebo treated
patients.14The overall incidence of EPS was also
lower in the aripiprazole group compared to halop-
eridol in the 52-week maintenance trial by Kujawa
et al.7 A meta analysis of 5 randomized 4 to 6-
week double-blind trials found the overall inci-
dence of EPS to be 21% and 44% for aripiprazole
and haloperidol respectively compared to 19% for
placebo. 13

Prolactin Level, QTcProlongation
In short-term clinical trials, clinically sig-
nificant increases in plasma prolactin levels oc-
curred in a similar proportion of patients (-3%)
who received aripiprazole versus placebo.2,14 Con-
versely, according to a meta-analysis of five short
term trials, aripiprazole significantly reduced
prolactin levels by 50% versus placebo, although
levels generally remained within normal limits.1
The incidence of QToprolongation was similar in
both aripiprazole and placebo groups.2,13

The recommended starting and target dose
of aripiprazole is 10-15 mg/day administered on a
once a day schedule without regard to meals.
Aripiprazole doses of 10 to 30 mg/day have been
evaluated and shown to be effective. However, in
clinical trials, doses higher than 10 to 15 mg/day
were no more effective than 10 or 15 mg/day. A
dosage increase should not be made before 2 weeks
of therapy, as this is the time needed to reach steady

Aripiprazole is about twice the price of
risperidone. A one month supply at a local retail
pharmacy is $357 and $506 for the 10 or 15 mg
and 20 mg tablets respectively. Bristol Myers
Squibb has put in place a patient assistance pro-
gram to aid patients who are unable to pay for the

Aripiprazole, is the first of a new class of
atypical antipsychotic drugs and has demonstrated
efficacy in clinical trials in patients with acute re-
lapse or stable chronic schizophrenia. It improves
symptoms at least as effectively as haloperidol and
to a similar extent as risperidone. In clinical trials,
aripiprazole's incidence of EPS was similar to pla-
cebo and the atypical agent risperidone, and oc-
curred less frequently than with haloperidol.

1. Carson WH, et al. Aripiprazole vs placebo in the treat-
ment of chronic schizophrenia. International Journal of
Neuropsychopharmacology 2002, Jun; 5 Suppl. 1; S187
2. Carson WH, Kane JM, et al. Efficacy and safety of
aripiprazole and haloperidol vs placebo in patients with
schizophrenia and schizoaffective disorder. Journal of
Clinical Psychiatry 2002, Sep; 63(9): 763-71.
3. Casey D, Saha AR, Ali MW, et al. Switching to aripipra-
zole monotherapy. International Journal of Neuropsycho-
pharmacology 2002 Jun; 5 Suppl. 1; S187
4. Corblatt B, Kern RS, Carson WH, et al. Neurocognitive
effects of aripiprazole vs olanzapine in stable psychosis.
International Journal of Neuropsychopharmacology 2002
Jun; 5 Suppl. 1:S185
5. Citrome L, Josiassen R, Bark N, et al. Pharmacokinetics
and safety of aripiprazole and concomitant mood stabiliz-
ers. International Journal of Neuropsychopharmacology
2002; 5 Suppl. 1 (Jun): S187
6. Daniel DG, Saha Ar, Ingenito G, et al. Aripiprazole, a
novel antipsychotic: overview of a phase II study result.

Pha rma Note Volume 18, Issue 8 May 2003


Volume 18, Issue 8 May 2003

International Journal of Neuropsychopharmacology 2000
Jul; 3 Suppl. 1: S157.
7. Kujawa M, Saha A, Ingenito G, et al. Aripiprazole for
long-term maintenance treatment of schizophrenia. In-
ternational Journal of Neuropsychopharmacology 2002
Jun; 5 Suppl. 1: S186-7
8. Lieberman J, Carson WH, Saha A, et al. Meta-analysis
of the efficacy of aripiprazole in schizophrenia. Interna-
tional Journal of Neuropsychopharmacology 2002 Jun; 5
Suppl. 1:S186
9. Mallikaarjun S, Ali MW, Salazar DE, et al. The effects
of age and gender on the pharmacokinetics of aripipra-
zole. Clin Pharmacol Ther 2002 Feb; 71(2):66
10. Mallikaarjun S, Salazar DE, Bramer SL. Pharmacokinet-
ics, tolerability, and safety of aripiprazole following sin-
gle and multiple oral dose administration. European
Neuropsychopharmacology 2000 Sep;10 Suppl. 3: 306-7.
11. Product Information: Abilify(aripiprazole). Bristol-
Myers Squibb Company, Princeton, NJ (PI issued No-
vember 2002).
12. Shaun Jordan, Vuk Kprivica, Ruoyan Chen, Katsura Tot-
tori, Tetsuro Kikuchi, C. Anthony Altar. The antipsy-
chotic aripiprazole is a potent, partial agonist at the hu-
man 5-HT1Areceptor. European Journal of Pharmacol-
ogy 441 (2002) 137-140.
13. Stock E, Marder SR, Saha AR, et al. Safety and tolerabil-
ity meta-analysis of aripiprazole in schizophrenia. Inter-
national Journal of Neuropsychopharmacology 2002 Jun;
5 Suppl. 1:S186.
14. Yeung P, et al. Aripiprazole and risperidone versus pla-
cebo in schizophrenia [abstract]. Eur Psychiatry. 2002;17
supplyl 1): 102-3.
15. Petrie JL, et al. Aripiprazole, a new atypical antipsy-
chotic: phase 2 clinical trial results [poster]. Xth Euro-
pean College of Neuropsychopharmacology Congress.
September 13-17, 1997, Vienna, Austria.

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

John G. Gums Editor

R. Whit Curry, M.D. Associate Editor

John M. Tovar Assistant Editor


Ruthan White, Pharm.D. Candidate

Approximately 50 million Americans have
high blood pressure (>140/90 mmHg).1 According
to data from the National Health and Nutrition Ex-
amination Survey, Phase III, only 27% of these in-
dividuals control their blood pressure to <140/90
mmHg. Furthermore, only 41.5% of patients being
treated for hypertension achieve controlled blood
pressure.2 Left untreated, hypertension can lead to
death caused by cardiovascular events, cerebrovas-
cular accidents, and renal failure.3 Benicar
(olmesartan medoxomil) was approved by the FDA
in April of 2002 as a new treatment option for hy-
pertension and is marketed by Sankyo Pharmaceu-
ticals Inc.4
Olmesartan medoxomil is one of the newest
entries in the growing angtiotensin II receptor
blocker (ARB) class. Similarly to the angiotensin
converting enzyme inhibitors (ACE-I), ARBs block
the effects of the renin-angiotensin-aldosterone sys-
tem. However, they do so through a different
mechanism. Unlike ACE-I, ARBs block the effects
of angtiotensin II generated by alternate pathways
as well.3 In addition, ARB's do not block the
breakdown of bradykinin, a vasodilating sub-
stance.3 This article will address the pharmacology,
clinical trials, adverse effects, costs, and prescrib-
ing considerations of olmesartan medoximil.

Olmesartan selectively blocks angiotensin II
from binding to the AT1 receptor. By blocking the
ATi receptor, it reduces vascular resistance and
lowers blood pressure. Blocking the AT1 receptors
does inhibit the negative feedback of angiotensin II
on renin secretion This results in an increase in
renin activity and circulating angiotensin II levels.
However, this does not overcome the effect of
olmesartan on blood pressure.6 Because its actions
are independent of the pathways for angiotensin II
synthesis, it provides a more specific and complete
RAS blockade compared to ACE inhibitors.

Pha ma ote olue 18 Isue 8May200


Volume 18, Issue 8 May 2003

Table 1. Summary of olmesartan medoxomil's hypertension clinical studies

Authors Study Design N Treatment Groups Clinical Findings

Neutal et al. R, DB, PC, PG, 2693 OLM 2.5mg, 5mg, 10mg, 20mg, Mean change from baseline in DBP and
20017 MC 4-1i m' 80mg QD vs. PBO SBP was significantly greater in OLM
treated group than PBO treated group.
Neutal et al. R, DB, PC, PG, 334 OLM 5mg, 20mg, 80mg QD vs. There is no significant advantage of
20029 MC OLM 2.5mg, 10mg, 40mg BID PBO twice-daily dosing versus once-daily
Oparil et al. R, DB, PC, PG, 588 OLM 20mg QD vs. LOS 50mg QD, OLM showed a significant reduction
2001' MC VAL 80mg QD, IRB 150mg QD only in DBP vs. the others, reduction in
SBP was non-significant.
Chrysant et al. R, DB, PC, PG, 440 OLM 20mg QD vs. AML 5mg QD OLM showed efficacy similar to AML.
200211 MC vs. PBO
Ball et al. DB MC 351 OLM 10mg + HCTZ 25mg vs. Response was similar in both groups.
200112 R, DB, PG, MC ATE 50mg + HCTZ 25mg
Ball et al. R, DB,PC, PG, 430 Starting dose: OLM 5mg + PBO QD OLM was superior to CAP.
200112 MC vs. CAP 12.5mg BID
R=randomized, DB=double-blind, PC placebo-controlled, PG parallel-group, MC multicenter, OLM olmesartan, PBO placebo, DBP diastolic blood pressure
SBP systolic blood pressure, LOS losartan, VAL valsartan, IRB irbesartan, HCTZ= hydrochlorothiazide, AML amlodipine, ATE atenolol, CAP captopril

Olmesartan medoxomil is administered
orally. In the gastrointestinal tract, olmesartan me-
doxomil is converted to active olmesartan. No fur-
ther metabolism occurs. The absolute bioavailabil-
ity of olmesartan is -26%. It takes 1-2 hours to
reach peak concentrations. Food does not affect the
bioavailability of olmesartan. It is eliminated in a
biphasic manner with a terminal elimination half-
life of approximately 13 hours. Olmesartan reaches
steady-state levels within 3-5 days. No accumula-
tion in plasma occurs with once-daily dosing.
Olmesartan is highly bound to plasma proteins
(99%). The volume of distribution is about 17 li-
ters. About 35-50% of the unchanged drug is elimi-
nated in the urine, while the remainder is elimi-
nated in the feces via the bile.6'7
The pharmacokinetics of olmesartan are not
significantly different between the elderly and those
younger than 65 years. In patients with renal insuf-
ficiency, serum concentrations of olmesartan were
elevated compared to subjects with normal renal
function. In patients undergoing hemodialysis the
pharmacokinetics of olmesartan have not been stud-
ied. In patients with hepatic impairment, increases
in AUC of 60% were observed.6

Clinical Trials
The efficacy and safety data for olmesartan
were demonstrated in seven placebo-controlled


studies involving patients with essential hyperten-
sion.7 To summarize the efficacy data, patients
treated with 20 mg/day of olmesartan had mean re-
ductions of 12 mmHg in DBP and 15 mmHg in
SBP after 6-12 weeks of treatment.7 The antihyper-
tensive response to olmesartan was seen within 2
weeks of initiating treatment with a maximum
benefit seen at 4 weeks after initiation of therapy.7
The drug is equally effective in older patients as it
was in younger patients.
Neutal et al.9 studied the effect of once-
daily versus twice-daily dosing of olmesartan.
Treatment with olmesartan showed a significant re-
duction in DBP and SBP versus placebo. Both
olmesartan dosing regimens reduced DBP and SBP
significantly compared to placebo. The twice-daily
dosing showed no clinical advantage over once-
daily dosing.8'9
Olmesartan has also been studied against
other leading ARB's. Oparil et al.10 compared the
recommended starting doses of olmesartan, losar-
tan, valsartan, and irbesartan in patients with essen-
tial hypertension. This study showed that olmesar-
tan had a significantly greater reduction in DBP
over the other three ARB's. It also showed a nu-
merically greater reduction in SBP compared to the
others, however, this reduction was not found to be
The antihypertensive effect of olmesartan
was studied against other antihypertensive agents.

Volume 18, Issue 8 May 2003



Table 2. Treatment-emergent adverse events reported in > 1% of hypertensive patients
controlled, monotherapy trials of olmesartan medoxomil7

in double-blinded, placebo-

Olmesartan Medoxomil Placebo
Adverse Events
N % N %
Headache 141 5.6 40 7.2
URT infection 83 3.3 27 4.9
Influenza-like symptoms 79 3.1 16 2.9
Dizziness 70 2.8 5 0.9
Bronchitis 51 2.0 10 1.8
Rhinitis 40 1.6 9 1.6
Increased CPK 40 1.6 6 1.1
Back pain 41 1.6 8 1.4
Pharyngitis 33 1.3 6 1.1
Hyperglycemia 32 1.3 15 2.7
Sinutsitis 29 1.1 11 2.0
Hypertriglyceridemia 29 1.1 6 1.1
Diarrhea 27 1.1 4 0.7
Peripheral edema 20 0.8 6 1.1
Patients experiencing >1 adverse event 1,071 42.2 237 42.7
N=number of patients; URT-upper respiratory tract; CPK=creatine phosphokinase

When comparing the efficacy of olmersartan to am-
lodipine besylate, both active treatments showed
similar levels of blood pressure reduction. Ambula-
tory SBP/DBP was reduced by 2.5/1.6 mmHg in
the placebo group, 12.9/7.4 mmHg in the amlodip-
ine group, and 13.0/8.2 mmHg in the olmesartan
group. The only difference in adverse events was a
significantly higher incidence of nausea with am-
lodipine (2.7%) vs. olmesartan (0%) or placebo.1l
Ball et al.12 compared the efficacy of olme-
sartan plus HCTZ to atenolol plus HCTZ. Doubling
of the dose was allowed at week 4 if needed. In
both treatment groups, decreases of about 12
mmHg in sitting DBP and 14-55 mmHg in sitting
SBP were achieved after 2 weeks of treatment. Dif-
ferences between the treatments at weeks 2, 4 and 8
were not statistically significant, although at the
early (weeks 2 and 4) visits, the mean decreases
from those on atenolol were slightly higher than
those on olmesartan.
Ball et al.12 also studied olmesartan against
captopril. Doubling of the dose was allowed at
weeks 4 and 8 for up to 12 weeks if required. There
were more patients titrated to higher doses in the
captopril group than in the olmesartan group. By
week 12, only 14% of captopril patients remained
on the starting dose, compared with 42% of olme-
sartan patients. The mean change in SBP/DBP for

the olmesartan group was -14.7/-9.9 versus -7.1/6.8
in the captopril group. Olmesartan was statistically
significantly superior to captopril for reducing both
systolic and diastolic blood pressure.

Dosing and Administration
Olmesartan medoxomil is available as 5, 20,
and 40 mg tablets. The usual starting dose is 20 mg
once daily when used as monotherapy, which may
be increased to 40 mg/day if a further decrease in
blood pressure is needed after 2 weeks of therapy.
Doses higher than 40 mg/day do not have a greater
effect in lowering blood pressure and there is no
advantage to twice daily dosing. If blood pressure
is not controlled by olmesartan alone, it may be ad-
ministered with other antihypertensive agents. No
initial dosage adjustments are needed for elderly
patients, patients with mild to moderate hepatic im-
pairment, or patients with mild to moderate renal
impairment. Olmesartan may be administered with-
out regard to food.6

When pregnancy is detected, Benicar
should be discontinued. It is classified as a preg-
nancy category C agent for the first trimester and D
in the second and third trimesters. Drugs that di-
rectly act on the RAS can cause fetal and neonatal

Pharm NteVoum 1, sse My 00


Volume 18, Issue 8 May 2003

Table 3. Cost comparison of BenicarM 5, 20, 40 mg/day

Pharmacy Price
Retail (chain) $43.59
Independent $48.43
Internet $36.99
Mean Price $43.00

morbidity and death when administered to pregnant
women. It is not known whether olmesartan is ex-
creted in human milk, but it is secreted in low con-
centrations in lactating rats.6
Therapy should be initiated at a low dose
and under close medical supervision for patients
with possible volume or salt depletion. These pa-
tients may develop symptomatic hypotension after
the initiation of treatment.6

Adverse Events
In an integrated analysis of seven placebo-
controlled studies, the incidence of adverse events
(AE) was similar for olmesartan medoxomil and
placebo. Table 2 shows the adverse events reported
by >1% of patients in either treatment group. The
only AE that was reported to occur at a frequency
of >1% in olmesartan-treated patients compared to
placebo was dizziness. No statistically significant
relationship between olmesartan medoxomil and
any severe AE was identified.7s'

Drug Interactions
There have been no clinically significant
drug interactions shown with olmesartan me-
doxomil. Because olmesartan does not undergo me-
tabolism by CYP450, there are no interactions re-
ported with drugs that inhibit, induce or are me-
tabolized by those enzymes. When olmesartan me-
doxomil was given with digoxin or warfarin in
healthy volunteers no significant drug interactions
were noted. Bioavailabity of olmesartan was not
significantly altered by the co-administration of

The retail cost for a 30-day supply is sum-
marized in Table 3. There is no variation in price
among the different strengths.

Olmesartan medoxomil is one of the newest
ARB's to enter the market for the treatment of hy-
pertension. It is as efficacious as other antihyper-
tensive agents including amlodipine and atenolol,
as well as other drugs in its class. Olmesartan is
generally well tolerated and has not been associated
with any serious complications. Dizziness was the
most common adverse event noted. Because it is
metabolized in the GI tract only, it has no signifi-
cant drug interactions associated with its use. It
should not be used in women who are pregnant or
may become pregnant. Caution should be used in
patients who are volume depleted.

1. The Sixth Report of the National Committee on detec-
tion, evaluation, and treatment of high blood pressure
(JNC-VI). Arch Intern Med 1997;157:2413-2446.
2. Oparil S, et al. Hypertension control rates and hyperten-
sive subtypes in the year 2000: An analysis comparing
the clinics-based PATH and population-based NHANES
III surveys (abstract). Am J Hypertens 2002;15:144A.
3. Hawkins DW, et al. Hypertension. In: Depiro JT, editor.
Pharmacotherapy: A Pathophysiologic Approach. 4th ed.
Stamford (CT): Appleton & Lange; 1999. p. 131-152.
4. FDA grants marketing approval for BenicarTM for treat-
ment of hypertension. April 26, 2002. Available from:
URL: http://www.benicar.com/b in the news/fda.asp?
5. Smith D. Strategies to meet lower blood pressure goals
with a new standard in angiotensin II receptor blockade.
Am J of Hypertens. 2002;15:S108-S114.
6. BenicarTM Product Information. Sankyo Pharmaceuticals
Inc., 2002.
7. Neutal JM. Clinical studies of CS-866, the newest angio-
tensin II receptor antagonist. Am J Cardiol 2001;87
8. Smith DH. Strategies to meet lower blood pressure goals
with a new standard in angiotensin II receptor blockade.
Am J Hypertens 2002;15 Supp 1:S108-S114.
9. Neutal JM, Elliott WJ, et al. Antihypertensive efficacy of
olmesartan medoxomil, a new angiotensin II receptor an-
tagonist, as assessed by ambulatory blood pressure meas-
urements. J Clin Hypertens 2002;4: 325-330.
10. Oparil S, et al. Comparative efficacy of olmesartan, losar-
tan, valsartan, and irbesartan in the control of essential
hypertension. J Clin Hypertens 2001;3:283-291.
11. Chrysant SG, Marbury T. The antihypertensive efficacy
and safety of olmesartan medoxomil compared with am-
lodipine for mild-to-moderate hypertension. Am J Hy-
pertens 2002;15: 57A.
12. Ball KJ, Williams PA, Stumpe KO. Relative Efficacy of
an angiotensin II antagonist compared with other anti-
hypertensive agents. Olmesartan medoxomil versus anti-
hypertensives. J Hypertens 2001;19 (Suppll):S49-S56.

Pha rma Note Volume 18, Issue 8 May 2003


Volume 18, Issue 8 May 2003

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