HIGHLIGHTS OF PRESCRIBING INFORMATION ------------------DOSAGE FORMS AND STRENGTHS-----------------

These highlights do not include all the information needed to use AZOR
safely and effectively. See full prescribing information for AZOR. Tablets: (amlodipine/olmesartan medoxomil content) 5/20 mg; 10/20 mg; 5/40
mg; and 10/40 mg (3).
AZOR (amlodipine and olmesartan medoxomil) tablets, for oral use -------------------------CONTRAINDICATIONS--------------------------­
Initial U.S. Approval: 2007
• None (4).
USE IN PREGNANCY
See full prescribing information for complete boxed warning. -----------------WARNINGS AND PRECAUTIONS---------------------
When pregnancy is detected, discontinue Azor as soon as • Hypotension in volume- or salt-depleted patients with treatment
possible. When used in pregnancy during the second and third initiation may be anticipated. Start treatment under close supervision
trimesters, drugs that act directly on the renin-angiotensin (5.2).
system can cause injury and even death to the developing fetus • Increased angina or myocardial infarction with calcium channel blockers
(5.1). may occur upon dosage initiation or increase (5.4).
-----------------------RECENT MAJOR CHANGES------------------------- • Impaired renal function: changes in renal function may be anticipated in
susceptible individual (5.6).
Indications and Usage (1) 11/2011
------------------------ADVERSE REACTIONS----------------------------
------------------------INDICATIONS AND USAGE-------------------------
Most common adverse reaction (incidence ≥3%) is edema (6.1).
• Azor is a dihydropyridine calcium channel blocker and angiotensin II
receptor blocker combination product indicated for the treatment of To report SUSPECTED ADVERSE REACTIONS, contact Daiichi
hypertension, alone or with other antihypertensive agents, to lower blood Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-332-1088 or
pressure. Lowering blood pressure reduces the risk of fatal and nonfatal www.fda.gov/medwatch.
cardiovascular events, primarily strokes and myocardial infarctions. (1).
• Azor is indicated as initial therapy in patients likely to need multiple ------------------------DRUG INTERACTIONS----------------------------
antihypertensive agents to achieve their blood pressure goals (1). Olmesartan medoxomil (7.3):
• Nonsteroidal anti-inflammatory drugs (NSAIDS may lead to increased
-------------------DOSAGE AND ADMINISTRATION------------------
risk of renal impairment and loss of antihypertensive effect.
• Substitute Azor for its individually titrated components for patients on -----------------USE IN SPECIFIC POPULATIONS--------------------­
amlodipine and olmesartan medoxomil. Azor may also be given with
increased amounts of amlodipine, olmesartan medoxomil, or both, as • In patients with an activated renin-angiotensin system, such as volume-
needed (2). or salt-depletion, renin-angiotensin-aldosterone system (RAAS) blockers
• Azor may be used to provide additional blood pressure lowering for such as olmesartan medoxomil can cause excessive hypotension. In
patients not adequately controlled with amlodipine (or another susceptible patients, e.g., with renal artery stenosis, RAAS blockers can
dihydropyridine calcium channel blocker) alone or with olmesartan cause renal failure (5.2, 5.6).
medoxomil (or another angiotensin receptor blocker) alone (2). • Start amlodipine alone or add amlodipine at 2.5 mg in patients ≥75 years
• Dosage may be increased after 2 weeks to a maximum dose of 10/40 mg old or in hepatically impaired patients. Elderly and patients with hepatic
once daily, usually by increasing one component at a time but both impairment have decreased clearance of amlodipine. Initial therapy with
components can be raised to achieve more rapid control (2). Azor is not recommended in patients ≥75 years old or hepatically
• Maximum antihypertensive effects are attained within 2 weeks after a impaired patients (8.5, 8.6).
change in dose (2).
• Initial therapy: Initiate with 5/20 mg once daily for 1 to 2 weeks and See 17 for PATIENT COUNSELING INFORMATION
titrate as needed up to a maximum of 10/40 mg once daily (2).
Revised 11/2011
__________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS* 8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
WARNING—USE IN PREGNANCY 8.3 Nursing Mothers
1 INDICATIONS AND USAGE 8.4 Pediatric Use
2 DOSAGE AND ADMINISTRATION 8.5 Geriatric Use
3 DOSAGE FORMS AND STRENGTHS 8.6 Hepatic Impairment
4 CONTRAINDICATIONS 8.7 Renal Impairment
5 WARNINGS AND PRECAUTIONS 8.8 Black Patients
5.1 Fetal/Neonatal Morbidity and Mortality 10 OVERDOSAGE
5.2 Hypotension in Volume- or Salt-Depleted Patients 11 DESCRIPTION
5.3 Vasodilation 12 CLINICAL PHARMACOLOGY
5.4 Patients with Severe Obstructive Coronary Artery Disease 12.1 Mechanism of Action
5.5 Patients with Congestive Heart Failure 12.2 Pharmacodynamics
5.6 Patients with Impaired Renal Function 12.3 Pharmacokinetics
5.7 Patients with Hepatic Impairment 13 NONCLINICAL TOXICOLOGY
5.8 Laboratory Tests 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
6 ADVERSE REACTIONS 14 CLINICAL STUDIES
6.1 Clinical Trials Experience 14.1 Azor
6.2 Post-Marketing Experience 14.2 Amlodipine
7 DRUG INTERACTIONS 14.3 Olmesartan Medoxomil
7.1 Drug Interactions with Azor 16 HOW SUPPLIED/STORAGE AND HANDLING
7.2 Drug Interactions with Amlodipine 17 PATIENT COUNSELING INFORMATION
7.3 Drug Interactions with Olmesartan Medoxomil *Sections or subsections omitted from the full prescribing information are not listed
__________________________________________________________________________________________

Reference ID: 3043634

 FULL PRESCRIBING INFORMATION
Azor® (amlodipine and olmesartan medoxomil) tablets

USE IN PREGNANCY

When pregnancy is detected, discontinue Azor as soon as possible. When used in

pregnancy during the second and third trimesters, drugs that act directly on the

renin-angiotensin system can cause injury and even death to the developing fetus

[see Warning and Precautions (5.1)].

1 INDICATIONS AND USAGE

Azor is indicated for the treatment of hypertension, alone or with other

antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the
risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial
infarctions. These benefits have been seen in controlled trials of antihypertensive drugs
from a wide variety of pharmacologic classes including the class to which this drug
principally belongs. There are no controlled trials demonstrating risk reduction with Azor.

Control of high blood pressure should be part of comprehensive cardiovascular risk

management, including, as appropriate, lipid control, diabetes management, antithrombotic
therapy, smoking cessation, exercise, and limited sodium intake. Many patients will
require more than one drug to achieve blood pressure goals. For specific advice on goals
and management, see published guidelines, such as those of the National High Blood
Pressure Education Program’s Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with

different mechanisms of action, have been shown in randomized controlled trials to
reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood
pressure reduction, and not some other pharmacologic property of the drugs, that is
largely responsible for those benefits. The largest and most consistent cardiovascular
outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial
infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the
absolute risk increase per mmHg is greater at higher blood pressures, so that even modest
reductions of severe hypertension can provide substantial benefit. Relative risk reduction
from blood pressure reduction is similar across populations with varying absolute risk, so
the absolute benefit is greater in patients who are at higher risk independent of their
hypertension (for example, patients with diabetes or hyperlipidemia), and such patients
would be expected to benefit from more aggressive treatment to a lower blood pressure
goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in
black patients, and many antihypertensive drugs have additional approved indications and
effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may
guide selection of therapy.

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 Azor may also be used as initial therapy in patients who are likely to need multiple
antihypertensive agents to achieve their blood pressure goals.

Patients with moderate or severe hypertension are at relatively high risk for
cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure,
and vision problems, so prompt treatment is clinically relevant. The decision to use a
combination as initial therapy should be individualized and should be shaped by
considerations such as baseline blood pressure, the target goal, and the incremental
likelihood of achieving goal with a combination compared to monotherapy. Individual
blood pressure goals may vary based upon the patient’s risk.

Data from an 8-week, placebo-controlled, parallel-group factorial study [see Clinical

Studies (14.1)] provide estimates of the probability of reaching a blood pressure goal
with Azor compared to amlodipine or olmesartan medoxomil monotherapy. The
figures below provide estimates of the likelihood of achieving the targeted systolic or
diastolic blood pressure goals with Azor 10/40 mg compared with amlodipine or
olmesartan medoxomil monotherapy, based upon baseline systolic or diastolic blood
pressure. The curve of each treatment group was estimated by logistic regression
modeling from all available data of that treatment group. The right tail of each curve is
less reliable because of small numbers of subjects with high baseline blood pressures.

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 Figure 1: Probability of Achieving Systolic Blood Figure 2: Probability of Achieving Diastolic Blood

Pressure (SBP) < 140 mmHg at Week 8 With LOCF Pressure (DBP) < 90 mmHg at Week 8 With LOCF

Figure 3: Probability of Achieving Systolic Blood Figure 4: Probability of Achieving Diastolic Blood

Pressure (SBP) < 130 mmHg at Week 8 With LOCF Pressure (DBP) < 80 mmHg at Week 8 With LOCF

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 The figures above provide an approximation of the likelihood of reaching a targeted
blood pressure goal (e.g., Week 8 SBP <140 mmHg or <130 mmHg or a DBP
<90 mmHg or <80 mmHg) for the high-dose treatment groups evaluated in the study.
Azor 5/20 mg, the lowest dose combination treatment group, increases the probability
of reaching blood pressure goal compared with the highest dose monotherapies,
amlodipine 10 mg and olmesartan medoxomil 40 mg.

For example, a patient with a baseline blood pressure of 160/100 mmHg has about a
48% likelihood of achieving a goal of <140 mmHg (systolic) and a 51% likelihood of
achieving a goal of <90 mmHg (diastolic) on monotherapy with olmesartan medoxomil
40 mg, and about a 46% likelihood of achieving a goal of <140 mmHg (systolic) and a
60% likelihood of achieving a goal of <90 mmHg (diastolic) on monotherapy with
amlodipine 10 mg. The likelihood of achieving these same goals increases to 63%
(systolic) and 71% (diastolic) on Azor 5/20 mg, and to 68% (systolic) and 85%
(diastolic) on Azor 10/40 mg.

2 DOSAGE AND ADMINISTRATION

General Considerations
The side effects of olmesartan medoxomil are generally rare and apparently
independent of dose. Those of amlodipine are generally dose-dependent (mostly
edema).

Maximum antihypertensive effects are attained within 2 weeks after a change in dose.

Azor may be taken with or without food.

Azor may be administered with other antihypertensive agents.

Dosage may be increased after 2 weeks. The maximum recommended dose of Azor is
10/40 mg.

Replacement Therapy
Azor may be substituted for its individually titrated components.

When substituting for individual components, the dose of one or both of the
components can be increased if blood pressure control has not been satisfactory.

Add-on Therapy

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 Azor may be used to provide additional blood pressure lowering for patients not
adequately controlled with amlodipine (or another dihydropyridine calcium channel
blocker) alone or with olmesartan medoxomil (or another angiotensin receptor blocker)
alone.

Initial Therapy
The usual starting dose of Azor is 5/20 mg once daily. The dosage can be increased
after 1 to 2 weeks of therapy to a maximum dose of one 10/40 mg tablet once daily as
needed to control blood pressure [See Clinical Studies (14.1)].

Initial therapy with Azor is not recommended in patients ≥75 years old or with hepatic
impairment [See Warnings and Precautions (5.7) and Use in Specific Populations (8.5,
8.6)].

3 DOSAGE FORMS AND STRENGTHS

Azor tablets are formulated for oral administration in the following strength
combinations:
5/20 5/40 10/20 10/40
Amlodipine 5 5 10 10
equivalent (mg)
Olmesartan 20 40 20 40
medoxomil (mg)

4 CONTRAINDICATIONS
None.

5 WARNINGS AND PRECAUTIONS

5.1 Fetal/Neonatal Morbidity and Mortality
Olmesartan medoxomil. Drugs that act directly on the renin-angiotensin system can
cause fetal and neonatal morbidity and death when administered to pregnant women.
There have been several dozen cases reported in the world literature of patients who
were taking angiotensin converting enzyme inhibitors. When pregnancy is detected,
discontinue Azor as soon as possible.

During the second and third trimesters of pregnancy, these drugs have been associated
with fetal injury that includes hypotension, neonatal skull hypoplasia, anuria, reversible
or irreversible renal failure, and death. Oligohydramnios has also been reported,
presumably resulting from decreased fetal renal function; oligohydramnios in this
setting has been associated with fetal limb contractures, craniofacial deformation, and
hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent
ductus arteriosus have also been reported, although it is not clear whether these
occurrences were due to exposure to the drug.

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 These adverse effects do not appear to have resulted from intrauterine drug exposure
that has been limited to the first trimester. Mothers whose embryos and fetuses are
exposed to an angiotensin II receptor antagonist only during the first trimester should
be so informed. Nonetheless, when patients become pregnant, physicians should have
the patient discontinue the use of Azor as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to
a drug acting on the renin-angiotensin system will be found. In these rare cases, the
mothers should be apprised of the potential hazards to their fetuses and serial
ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, discontinue Azor unless it is considered life-saving for

the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical
profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients
and physicians should be aware, however, that oligohydramnios may not appear until
after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist

should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria
occurs, attention should be directed toward support of blood pressure and renal
perfusion. Exchange transfusion or dialysis may be required as means of reversing
hypotension and/or substituting for disordered renal function.

No teratogenic effects were observed when olmesartan medoxomil was administered to

pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum
recommended human dose (MRHD) on a mg/m2 basis) or pregnant rabbits at oral
doses up to 1 mg/kg/day (half the MRHD on a mg/m2 basis; higher doses could not be
evaluated for effects on fetal development as they were lethal to the does). In rats,
significant decreases in pup birth weight and weight gain were observed at doses
≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear
auricular, eruption of lower incisors, appearance of abdominal hair, descent of testes,
and separation of eyelids) and dose-dependent increases in the incidence of dilation of
the renal pelvis were observed at doses ≥8 mg/kg/day. The no observed effect dose for
developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of
40 mg/day.

5.2 Hypotension in Volume- or Salt-Depleted Patients

Olmesartan medoxomil. Symptomatic hypotension may be anticipated after initiation
of treatment with olmesartan medoxomil. Patients with an activated renin-angiotensin

Reference ID: 3043634

 system, such as volume- and/or salt-depleted patients (e.g., those being treated with
high doses of diuretics) may be particularly vulnerable. Initiate treatment with Azor
under close medical supervision. If hypotension does occur, place the patient in the
supine position and, if necessary, give an intravenous infusion of normal saline. A
transient hypotensive response is not a contraindication to further treatment, which
usually can be continued without difficulty once the blood pressure has stabilized.

5.3 Vasodilation
Amlodipine. Since the vasodilation attributable to amlodipine in Azor is gradual in
onset, acute hypotension has rarely been reported after oral administration.
Nonetheless, exercise caution, as with any other peripheral vasodilator, when
administering Azor, particularly in patients with severe aortic stenosis.

5.4 Patients with Severe Obstructive Coronary Artery Disease

Patients, particularly those with severe obstructive coronary artery disease, may
develop increased frequency, duration, or severity of angina or acute myocardial
infarction on starting calcium channel blocker therapy or at the time of dosage increase.
The mechanism of this effect has not been elucidated.

5.5 Patients with Congestive Heart Failure

Amlodipine. Amlodipine (5–10 mg per day) has been studied in a placebo-controlled
trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE
inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about
14 months. There was no overall adverse effect on survival or cardiac morbidity (as
defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization
for worsened heart failure). Amlodipine has been compared to placebo in four 8–12
week studies of patients with NYHA class II/III heart failure, involving a total of 697
patients. In these studies, there was no evidence of worsening of heart failure based on
measures of exercise tolerance, NYHA classification, symptoms, or LVEF.

5.6 Patients with Impaired Renal Function

Azor. There are no studies of Azor in patients with renal impairment.

Olmesartan medoxomil. Changes in renal function may be anticipated in susceptible

individuals treated with olmesartan medoxomil as a consequence of inhibiting the
renin-angiotensin-aldosterone system. In patients whose renal function may depend
upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe
congestive heart failure), treatment with angiotensin converting enzyme inhibitors and
angiotensin receptor antagonists has been associated with oliguria or progressive
azotemia and (rarely) with acute renal failure and/or death. Similar effects may occur in

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 patients treated with Azor because of the olmesartan medoxomil component [See
Clinical Pharmacology (12.3)].

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis,
increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There
has been no long-term use of olmesartan medoxomil in patients with unilateral or
bilateral renal artery stenosis, but similar effects would be expected with olmesartan
medoxomil and Azor.

5.7 Patients with Hepatic Impairment

Amlodipine. Since amlodipine is extensively metabolized by the liver and the plasma
elimination half-life (t½) is 56 hours in patients with severely impaired hepatic
function, exercise caution when administering Azor to patients with severe hepatic
impairment.

Patients with hepatic impairment have decreased clearance of amlodipine. Starting

amlodipine or adding amlodipine at 2.5 mg in hepatically impaired patients is
recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor
is not recommended in hepatically impaired patients [See Use in Specific Populations
(8.6)].

5.8 Laboratory Tests

Azor. There was a greater decrease in hemoglobin and hematocrit in the combination
product compared to either component. Other laboratory changes can usually be
attributed to either monotherapy component.

Amlodipine. In post-marketing experience, hepatic enzyme elevations have been

reported (6.2).

Olmesartan medoxomil. In post-marketing experience, increased blood creatinine

levels and hyperkalemia have been reported.

6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse
reaction rates observed in the clinical studies of a drug cannot be directly compared to
rates in the clinical studies of another drug and may not reflect the rates observed in
practice.

Azor

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 The data described below reflect exposure to Azor in more than 1600 patients
including more than 1000 exposed for at least 6 months and more than 700 exposed for
1 year. Azor was studied in one placebo-controlled factorial trial (See Section 14.1).
The population had a mean age of 54 years and included approximately 55% males.
Seventy-one percent were Caucasian and 25% were Black. Patients received doses
ranging from 5/20 mg to 10/40 mg orally once daily.

The overall incidence of adverse reactions on therapy with Azor was similar to that
seen with corresponding doses of the individual components of Azor, and to placebo.
The reported adverse reactions were generally mild and seldom led to discontinuation
of treatment (2.6% for Azor and 6.8% for placebo).

Edema
Edema is a known, dose-dependent adverse effect of amlodipine but not of olmesartan
medoxomil.

The placebo-subtracted incidence of edema during the 8-week, randomized,

double-blind treatment period was highest with amlodipine 10 mg monotherapy. The
incidence was significantly reduced when 20 mg or 40 mg of olmesartan medoxomil
was added to the 10 mg amlodipine dose.

Placebo-Subtracted Incidence of Edema During the Double-Blind Treatment Period

Olmesartan Medoxomil
Placebo 20 mg 40 mg
Placebo －* -2.4% 6.2%
Amlodipine 5 mg 0.7% 5.7% 6.2%
10 mg 24.5% 13.3% 11.2%
*
12.3% = actual placebo incidence

Across all treatment groups, the frequency of edema was generally higher in women
than men, as has been observed in previous studies of amlodipine.

Adverse reactions seen at lower rates during the double-blind period also occurred in
the patients treated with Azor at about the same or greater incidence as in patients
receiving placebo. These included hypotension, orthostatic hypotension, rash, pruritus,
palpitation, urinary frequency, and nocturia.

The adverse event profile obtained from 44 weeks of open-label combination therapy
with amlodipine plus olmesartan medoxomil was similar to that observed during the
8-week, double-blind, placebo-controlled period.

Initial Therapy

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 Analyzing the data described above specifically for initial therapy, it was observed that
higher doses of Azor caused slightly more hypotension and orthostatic symptoms, but
not at the recommended starting dose of Azor 5/20 mg. No increase in the incidence of
syncope or near syncope was observed. The incidences of discontinuation because of
any treatment emergent adverse events in the double blind phase are summarized in the
table below.

Discontinuation for any Treatment Emergent Adverse Event1

Olmesartan Medoxomil
Placebo 10 mg 20 mg 40 mg
Placebo 4.9% 4.3% 5.6% 3.1%
Amlodipine 5 mg 3.7% 0.0% 1.2% 3.7%
10 mg 5.5% 6.8% 2.5% 5.6%
1
Hypertension is counted as treatment failure and not as treatment emergent adverse event.
N=160-163 subjects per treatment group.

Amlodipine
Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and
foreign clinical trials. Most adverse reactions reported during therapy with amlodipine
were of mild or moderate severity. In controlled clinical trials directly comparing
amlodipine (N=1730) in doses up to 10 mg to placebo (N=1250), discontinuation of
amlodipine due to adverse reactions was required in only about 1.5% of amlodipine­
treated patients and about 1% of placebo-treated patients. The most common side
effects were headache and edema. The incidence (%) of dose-related side effects was
as follows:

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 Adverse Event Placebo 2.5 mg 5.0 mg 10.0 mg
N=520 N=275 N=296 N=268
Edema 0.6 1.8 3.0 10.8
Dizziness 1.5 1.1 3.4 3.4
Flushing 0.0 0.7 1.4 2.6
Palpitation 0.6 0.7 1.4 4.5

For several adverse experiences that appear to be drug- and dose-related, there was a
greater incidence in women than men associated with amlodipine treatment as shown
in the following table:

Adverse Event Placebo Amlodipine

Male=% Female=% Male=% Female=%

(N=914) (N=336) (N=1218) (N=512)
Edema 1.4 5.1 5.6 14.6
Flushing 0.3 0.9 1.5 4.5
Palpitation 0.9 0.9 1.4 3.3
Somnolence 0.8 0.3 1.3 1.6

Olmesartan medoxomil.
Olmesartan medoxomil has been evaluated for safety in more than
3825 patients/subjects, including more than 3275 patients treated for hypertension in
controlled trials. This experience included about 900 patients treated for at least
6 months and more than 525 treated for at least 1 year. Treatment with olmesartan
medoxomil was well tolerated, with an incidence of adverse events similar to that seen
with placebo. Events were generally mild, transient, and without relationship to the
dose of olmesartan medoxomil.

The overall frequency of adverse events was not dose-related. Analysis of gender, age,
and race groups demonstrated no differences between olmesartan medoxomil- and
placebo-treated patients. The rate of withdrawals due to adverse events in all trials of
hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with olmesartan
medoxomil and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the
only adverse event that occurred in more than 1% of patients treated with olmesartan
medoxomil and at a higher incidence in olmesartan medoxomil treated patients vs.
placebo was dizziness (3% vs 1%).

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 6.2 Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of the
individual components of Azor. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.

Amlodipine. The following post-marketing event has been reported infrequently where
a causal relationship is uncertain: gynecomastia. In post-marketing experience,
jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or
hepatitis), in some cases severe enough to require hospitalization, have been reported in
association with use of amlodipine.

Olmesartan medoxomil. The following adverse reactions have been reported in post-
marketing experience:
Body as a Whole: asthenia, angioedema, anaphylactic reactions, peripheral edema
Gastrointestinal: vomiting, diarrhea
Musculoskeletal: rhabdomyolysis
Urogenital System: acute renal failure
Skin and Appendages: alopecia, pruritus, urticaria

7 DRUG INTERACTIONS
7.1 Drug Interactions with Azor
The pharmacokinetics of amlodipine and olmesartan medoxomil are not altered when
the drugs are co-administered.

No drug interaction studies have been conducted with Azor and other drugs, although
studies have been conducted with the individual amlodipine and olmesartan
medoxomil components of Azor, as described below, and no significant drug
interactions have been observed.

7.2 Drug Interactions with Amlodipine

In vitro data indicate that amlodipine has no effect on the human plasma protein
binding of digoxin, phenytoin, warfarin, and indomethacin.

Effect of Other Agents on Amlodipine

Cimetidine: Co-administration of amlodipine with cimetidine did not alter the
pharmacokinetics of amlodipine.
Grapefruit juice: Co-administration of 240 mL of grapefruit juice with a single oral
dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the
pharmacokinetics of amlodipine.

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 Maalox® (antacid): Co-administration of the antacid Maalox® with a single dose of
amlodipine had no significant effect on the pharmacokinetics of amlodipine.
Sildenafil: A single 100 mg dose of sildenafil in subjects with essential
hypertension had no effect on the pharmacokinetic parameters of amlodipine.
When amlodipine and sildenafil were used in combination, each agent
independently exerted its own blood pressure lowering effect.

Effect of Amlodipine on Other Agents

Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine with 80 mg
of atorvastatin resulted in no significant change in the steady state pharmacokinetic
parameters of atorvastatin.
Digoxin: Co-administration of amlodipine with digoxin did not change serum
digoxin levels or digoxin renal clearance in normal volunteers.
Ethanol (alcohol): Single and multiple 10 mg doses of amlodipine had no
significant effect on the pharmacokinetics of ethanol.
Warfarin: Co-administration of amlodipine with warfarin did not change the
warfarin prothrombin response time.

In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-
blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual
nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and
oral hypoglycemic drugs.

7.3 Drug Interactions with Olmesartan Medoxomil

No significant drug interactions were reported in studies in which olmesartan
medoxomil was co-administered with digoxin or warfarin in healthy volunteers.

The bioavailability of olmesartan medoxomil was not significantly altered by the co­
administration of antacids [Al(OH)3/Mg(OH)2].

Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no
effects on P450 enzymes; thus, interactions with drugs that inhibit, induce, or are
metabolized by those enzymes are not expected.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2

Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume-depleted (including those on diuretic therapy), or

with compromised renal function, co-administration of NSAIDs, including selective
COX-2 inhibitors, with angiotensin II receptor antagonists, including olmesartan
medoxomil, may result in deterioration of renal function, including possible acute renal

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 failure. These effects are usually reversible. Monitor renal function periodically in
patients receiving olmesartan medoxomil and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan

medoxomil may be attenuated by NSAIDs including selective COX-2 inhibitors.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy
Olmesartan medoxomil. Pregnancy Categories C (first trimester) and D (second and
third trimesters). [See Warnings and Precautions (5.1)]

Amlodipine. No evidence of teratogenicity or other embryo/fetal toxicity was found

when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of
up to 10 mg amlodipine/kg/day (respectively about 10 and 20 times the maximum
recommended human dose of 10 mg amlodipine on a mg/m2 basis) during their
respective periods of major organogenesis. (Calculations based on a patient weight of
60 kg). However, litter size was significantly decreased (by about 50%) and the
number of intrauterine deaths was significantly increased (about 5-fold) in rats
receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for
14 days before mating and throughout mating and gestation. Amlodipine maleate has
been shown to prolong both the gestational period and the duration of labor in rats at
this dose. There are no adequate and well-controlled studies in pregnant women.
Amlodipine should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether the amlodipine or olmesartan medoxomil components of Azor
are excreted in human milk, but olmesartan is secreted at low concentration in the milk
of lactating rats. Because of the potential for adverse effects on the nursing infant, a
decision should be made whether to discontinue nursing or discontinue the drug, taking
into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of Azor in pediatric patients have not been established.

Amlodipine. The effect of amlodipine on blood pressure in patients less than 6 years of
age is not known.

Olmesartan medoxomil. Safety and effectiveness of olmesartan medoxomil in

pediatric patients have not been established.

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 8.5 Geriatric Use
Of the total number of subjects in the double-blind clinical study of Azor, 20%
(384/1940) were 65 years of age or older and 3% (62/1940) were 75 years or older. No
overall differences in safety or effectiveness were observed between subjects 65 years
of age or older and younger subjects.

Elderly patients have decreased clearance of amlodipine. Starting amlodipine or adding

amlodipine at 2.5 mg in patients ≥75 years old is recommended. The lowest dose of
Azor is 5/20 mg; therefore, initial therapy with Azor is not recommended in patients
≥75 years old.

Amlodipine. Reported clinical experience has not identified differences in responses

between the elderly and younger patients. In general, dose selection for an elderly
patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy. Elderly patients have decreased clearance of
amlodipine with a resulting increase of AUC of approximately 40% to 60%, and a
lower initial dose may be required.

Olmesartan medoxomil. Of the total number of hypertensive patients receiving

olmesartan medoxomil in clinical studies, more than 20% were 65 years of age and
over, while more than 5% were 75 years of age and older. No overall differences in
effectiveness or safety were observed between elderly patients and younger patients.
Other reported clinical experience has not identified differences in responses between
the elderly and younger patients, but greater sensitivity of some older individuals
cannot be ruled out.

8.6 Hepatic Impairment

There are no studies of Azor in patients with hepatic insufficiency, but both amlodipine
and olmesartan medoxomil show moderate increases in exposure in patients with
hepatic impairment. Use caution when administering Azor to patients with severe
hepatic impairment.

Patients with hepatic impairment have decreased clearance of amlodipine. Starting

amlodipine or adding amlodipine at 2.5 mg in patients with hepatic impairment is
recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor
is not recommended in hepatically impaired patients.

8.7 Renal Impairment

There are no studies of Azor in patients with renal impairment.

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 Amlodipine. The pharmacokinetics of amlodipine are not significantly influenced by
renal impairment. Patients with renal failure may therefore receive the usual initial
dose.

Olmesartan medoxomil. Patients with renal insufficiency have elevated serum

concentrations of olmesartan compared with patients with normal renal function. After
repeated dosing, AUC was approximately tripled in patients with severe renal
impairment (creatinine clearance <20 mL/min). No initial dosage adjustment is
recommended for patients with moderate to marked renal impairment (creatinine
clearance <40 mL/min).

8.8 Black Patients

Of the total number of subjects in the double-blind clinical study of Azor, 25%
(481/1940) were black patients. Azor was effective in treating black patients (usually a
low-renin population), and the magnitude of blood pressure reduction in black patients
approached that observed for non-black patients.

10 OVERDOSAGE
There is no information on overdosage with Azor in humans.

Amlodipine. Single oral doses of amlodipine maleate equivalent to 40 mg

amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths.
Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or
higher in dogs (11 or more times the maximum recommended human dose on a mg/m2
basis) caused a marked peripheral vasodilation and hypotension.

Overdosage might be expected to cause excessive peripheral vasodilation with marked

hypotension and possibly a reflex tachycardia. In humans, experience with intentional
overdosage of amlodipine is limited.

If massive overdose should occur, active cardiac and respiratory monitoring should be
instituted. Frequent blood pressure measurements are essential. Should hypotension
occur, cardiovascular support including elevation of the extremities and the judicious
administration of fluids should be initiated. If hypotension remains unresponsive to
these conservative measures, administration of vasopressors (such as phenylephrine)
should be considered with attention to circulating volume and urine output. Intravenous
calcium gluconate may help to reverse the effects of calcium entry blockade. As
amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

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 Olmesartan medoxomil. Limited data are available related to overdosage in humans.
The most likely manifestations of overdosage would be hypotension and tachycardia;
bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. If
symptomatic hypotension should occur, supportive treatment should be initiated. The
dialyzability of olmesartan is unknown.

11 DESCRIPTION
Azor, provided as a tablet for oral administration, is a combination of the calcium
channel blocker (CCB) amlodipine besylate and the angiotensin II receptor blocker
(ARB) olmesartan medoxomil.

The amlodipine besylate component of Azor is chemically described as 3-ethyl-5­

methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5­
pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is
C20H25ClN2O5•C6H6O3S.

Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from

the gastrointestinal tract.

The olmesartan medoxomil component of Azor is chemically described as 2,3­

dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5­
ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate. Its empirical formula is
C29H30N6O6.

The structural formula for amlodipine besylate is:

The structural formula for olmesartan medoxomil is:

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 Azor contains amlodipine besylate, a white to off-white crystalline powder, and
olmesartan medoxomil, a white to light yellowish-white powder or crystalline powder.
The molecular weights of amlodipine besylate and olmesartan medoxomil are 567.1
and 558.59, respectively. Amlodipine besylate is slightly soluble in water and sparingly
soluble in ethanol. Olmesartan medoxomil is practically insoluble in water and
sparingly soluble in methanol.

Each tablet of Azor also contains the following inactive ingredients: silicified
microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and
magnesium stearate. The color coatings contain polyvinyl alcohol, macrogol/
polyethylene glycol 3350, titanium dioxide, talc, iron oxide yellow (5/40 mg,
10/20 mg, 10/40 mg tablets), iron oxide red (10/20 mg and 10/40 mg tablets), and iron
oxide black (10/20 mg tablets).

12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Azor. Azor is a combination of two antihypertensive drugs: a dihydropyridine calcium
antagonist (calcium ion antagonist or slow-channel blocker), amlodipine besylate, and
an angiotensin II receptor blocker, olmesartan medoxomil. The amlodipine component
of Azor inhibits the transmembrane influx of calcium ions into vascular smooth muscle
and cardiac muscle, and the olmesartan medoxomil component of Azor blocks the
vasoconstrictor effects of angiotensin II.

Amlodipine. Experimental data suggests that amlodipine binds to both dihydropyridine

and nonhydropyridine binding sites. The contractile processes of cardiac muscle and
vascular smooth muscle are dependent upon the movement of extracellular calcium

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 ions into these cells through specific ion channels. Amlodipine inhibits calcium ion
influx across cell membranes selectively, with a greater effect on vascular smooth
muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected
in vitro but such effects have not been seen in intact animals at therapeutic doses.
Serum calcium concentration is not affected by amlodipine. Within the physiologic pH
range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with
the calcium channel receptor is characterized by a gradual rate of association and
dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth

muscle to cause a reduction in peripheral vascular resistance and reduction in blood
pressure.

Olmesartan medoxomil. Angiotensin II is formed from angiotensin I in a reaction

catalyzed by angiotensin converting enzyme (ACE, kininase II). Angiotensin II is the
principal pressor agent of the renin-angiotensin system, with effects that include
vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac
stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor
effects of angiotensin II by selectively blocking the binding of angiotensin II to the
AT1 receptor in vascular smooth muscle. Its action is, therefore, independent of the
pathways for angiotensin II synthesis.

An AT2 receptor is found also in many tissues, but this receptor is not known to be
associated with cardiovascular homeostasis. Olmesartan has more than a 12,500-fold
greater affinity for the AT1 receptor than for the AT2 receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the
biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used
to treat hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a
reaction also catalyzed by ACE. Because olmesartan does not inhibit ACE
(kininase II), it does not affect the response to bradykinin. Whether this difference has
clinical relevance is not yet known.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of

angiotensin II on renin secretion, but the resulting increased plasma renin activity and
circulating angiotensin II levels do not overcome the effect of olmesartan on blood
pressure.

12.2 Pharmacodynamics

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 Amlodipine. Following administration of therapeutic doses to patients with
hypertension, amlodipine produces vasodilation resulting in a reduction of supine and
standing blood pressures. These decreases in blood pressure are not accompanied by a
significant change in heart rate or plasma catecholamine levels with chronic dosing.

With chronic once daily oral administration, antihypertensive effectiveness is

maintained for at least 24 hours. Plasma concentrations correlate with effect in both
young and elderly patients. The magnitude of reduction in blood pressure with
amlodipine is also correlated with the height of pretreatment elevation; thus,
individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about
a 50% greater response than patients with mild hypertension (diastolic pressure
90-104 mmHg). Normotensive subjects experienced no clinically significant change in
blood pressures (+1/-2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of amlodipine

resulted in a decrease in renal vascular resistance and an increase in glomerular
filtration rate and effective renal plasma flow without change in filtration fraction or
proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac

function at rest and during exercise (or pacing) in patients with normal ventricular
function treated with amlodipine have generally demonstrated a small increase in
cardiac index without significant influence on dP/dt or on left ventricular end diastolic
pressure or volume. In hemodynamic studies, amlodipine has not been associated with
a negative inotropic effect when administered in the therapeutic dose range to intact
animals and man, even when co-administered with beta-blockers to man. Similar
findings, however, have been observed in normals or well-compensated patients with
heart failure with agents possessing significant negative inotropic effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in

intact animals or man. In clinical studies in which amlodipine was administered in
combination with beta-blockers to patients with either hypertension or angina, no
adverse effects on electrocardiographic parameters were observed.

Olmesartan medoxomil. Olmesartan medoxomil doses of 2.5 mg to 40 mg inhibit the

pressor effects of angiotensin I infusion. The duration of the inhibitory effect was
related to dose, with doses of olmesartan medoxomil >40 mg giving >90% inhibition at
24 hours.

Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity

(PRA) increase after single and repeated administration of olmesartan medoxomil to

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 healthy subjects and hypertensive patients. Repeated administration of up to 80 mg
olmesartan medoxomil had minimal influence on aldosterone levels and no effect on
serum potassium.

12.3 Pharmacokinetics
The pharmacokinetics of amlodipine and olmesartan medoxomil from Azor are
equivalent to the pharmacokinetics of amlodipine and olmesartan medoxomil when
administered separately. The bioavailability of both components is well below 100%,
but neither component is affected by food. The effective half-lives of amlodipine
(45±11 hours) and olmesartan (7±1 hours) result in a 2- to 3- fold accumulation for
amlodipine and negligible accumulation for olmesartan with once-daily dosing.

Amlodipine. After oral administration of therapeutic doses of amlodipine, absorption

produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability
is estimated as between 64% and 90%.

Olmesartan medoxomil. Olmesartan medoxomil is rapidly and completely bioactivated

by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. The
absolute bioavailability of olmesartan medoxomil is approximately 26%. After oral
administration, the peak plasma concentration (Cmax) of olmesartan is reached after 1 to
2 hours. Food does not affect the bioavailability of olmesartan medoxomil.

Distribution
Amlodipine. Ex vivo studies have shown that approximately 93% of the circulating
drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of
amlodipine are reached after 7 to 8 days of consecutive daily dosing.

Olmesartan medoxomil. The volume of distribution of olmesartan is approximately

17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red
blood cells. The protein binding is constant at plasma olmesartan concentrations well
above the range achieved with recommended doses.

In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed
across the placental barrier in rats and was distributed to the fetus. Olmesartan was
distributed to milk at low levels in rats.

Metabolism and Excretion

Amlodipine. Amlodipine is extensively (about 90%) converted to inactive metabolites
via hepatic metabolism. Elimination from the plasma is biphasic with a terminal

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 elimination half-life of about 30 to 50 hours. Ten percent of the parent compound and
60% of the metabolites are excreted in the urine.

Olmesartan medoxomil. Following the rapid and complete conversion of olmesartan

medoxomil to olmesartan during absorption, there is virtually no further metabolism of
olmesartan. Total plasma clearance of olmesartan is 1.3 L/h, with a renal clearance of
0.6 L/h. Approximately 35% to 50% of the absorbed dose is recovered in urine while
the remainder is eliminated in feces via the bile.

Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination

half-life of approximately 13 hours. Olmesartan shows linear pharmacokinetics
following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg.
Steady-state levels of olmesartan are achieved within 3 to 5 days and no accumulation
in plasma occurs with once-daily dosing.

Geriatric
The pharmacokinetic properties of Azor in the elderly are similar to those of the
individual components.

Amlodipine. Elderly patients have decreased clearance of amlodipine with a resulting

increase in AUC of approximately 40% to 60%, and a lower initial dose may be
required.

Olmesartan medoxomil. The pharmacokinetics of olmesartan medoxomil were studied

in the elderly (≥65 years). Overall, maximum plasma concentrations of olmesartan
were similar in young adults and the elderly. Modest accumulation of olmesartan was
observed in the elderly with repeated dosing; AUCѕѕ, τ was 33% higher in elderly
patients, corresponding to an approximate 30% reduction in CLR.

Pediatric
Amlodipine. Sixty-two hypertensive patients aged 6 to 17 years received doses of
amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of
distribution were similar to values in adults.

Olmesartan medoxomil. The pharmacokinetics of olmesartan medoxomil have not

been investigated in patients <18 years of age.

Gender

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 Population pharmacokinetic analysis indicated that female patients had approximately
15% smaller clearances of olmesartan than male patients. Gender had no effect on the
clearance of amlodipine.

Olmesartan medoxomil. Minor differences were observed in the pharmacokinetics of

olmesartan medoxomil in women compared to men. AUC and Cmax were 10% to 15%
higher in women than in men.

Renal Insufficiency
Amlodipine. The pharmacokinetics of amlodipine are not significantly influenced by
renal impairment. Patients with renal failure may therefore receive the usual initial
dose.

Olmesartan medoxomil. In patients with renal insufficiency, serum concentrations of

olmesartan were elevated compared to subjects with normal renal function. After
repeated dosing, the AUC was approximately tripled in patients with severe renal
impairment (creatinine clearance <20 mL/min). The pharmacokinetics of olmesartan
medoxomil in patients undergoing hemodialysis has not been studied. No initial dosage
adjustment is recommended for patients with moderate to marked renal impairment
(creatinine clearance <40 mL/min).

Hepatic Insufficiency
Amlodipine. Patients with hepatic insufficiency have decreased clearance of
amlodipine with a resulting increase in AUC of approximately 40% to 60%.

Olmesartan medoxomil. Increases in AUC0-∞ and Cmax were observed in patients with
moderate hepatic impairment compared to those in matched controls, with an increase
in AUC of about 60%.

Heart Failure
Amlodipine. Patients with heart failure have decreased clearance of amlodipine with a
resulting increase in AUC of approximately 40% to 60%.

13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Amlodipine. Rats and mice treated with amlodipine maleate in the diet for up to two
years, at concentrations calculated to provide daily dosage levels of amlodipine 0.5,
1.25, and 2.5 mg/kg/day showed no evidence of a carcinogenic effect of the drug. For
the mouse, the highest dose was, on a mg/m2 basis, similar to the maximum
recommended human dose (MRHD) of amlodipine 10 mg/day. For the rat, the highest

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 dose was, on a mg/m2 basis, about two and a half times the MRHD. (Calculations based
on a 60 kg patient.)

Mutagenicity studies conducted with amlodipine maleate revealed no drug related

effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with amlodipine maleate
(males for 64 days and females for 14 days prior to mating) at doses of amlodipine up
to 10 mg/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m2 basis).

Olmesartan medoxomil. Olmesartan was not carcinogenic when administered by

dietary administration to rats for up to 2 years. The highest dose tested
(2000 mg/kg/day) was, on a mg/m2 basis, about 480 times the maximum recommended
human dose (MRHD) of 40 mg/day. Two carcinogenicity studies conducted in mice, a
6-month gavage study in the p53 knockout mouse and a 6-month dietary administration
study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about
120 times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan.
Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian
hamster embryo cell transformation assay and showed no evidence of genetic toxicity
in the Ames (bacterial mutagenicity) test. However, both were shown to induce
chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested
positive for thymidine kinase mutations in the in vitro mouse lymphoma assay.
Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse
intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test)
at oral doses of up to 2000 mg/kg (olmesartan not tested).

Fertility of rats was unaffected by administration of olmesartan at dose levels as high

as 1000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun
2 (female) or 9 (male) weeks prior to mating.

14 CLINICAL STUDIES
14.1 Azor
An 8-week multicenter, randomized, double-blind, placebo controlled, parallel group
factorial study in patients with mild to severe hypertension was conducted to determine
if treatment with Azor was associated with clinically significant reduction in blood
pressure compared to the respective monotherapies. The study randomized
1940 patients equally to one of the following 12 treatment arms: placebo, monotherapy
treatment with amlodipine 5 mg or 10 mg, monotherapy treatment with olmesartan
medoxomil 10 mg, 20 mg, or 40 mg, or combination therapy with amlodipine/
olmesartan medoxomil at doses of 5/10 mg, 5/20 mg, 5/40 mg, 10/10 mg, 10/20 mg,

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 and 10/40 mg. Patients discontinued their prior antihypertensive treatment. The mean
baseline blood pressure of the study population was 164/102 mmHg. Of the total
cohort, 970 patients were treated with the combination as initial therapy.

Treatment with Azor resulted in statistically significant greater reductions in diastolic

and systolic blood pressure compared to the respective monotherapy components.

The following table presents the results for mean reduction in seated systolic and
diastolic blood pressure following 8 weeks of treatment with Azor. Placebo-adjusted
reductions from baseline in blood pressure were progressively greater with increases in
dose of both amlodipine and olmesartan medoxomil components of Azor.

Reduction in Seated Systolic/Diastolic Blood Pressure (mmHg): Combination Therapy vs.

Monotherapy Components (Double-Blind Treatment Period)
Olmesartan medoxomil
(mmHg) Placebo 10 mg 20 mg 40 mg
Mean Change -5/-3 -12/-8 -14/-9 -16/-10
Placebo
Placebo-Adjusted Mean Change -- -8/-5 -10/-6 -13/-7
Amlodipine

Mean Change -15/-9 -24/-14 -24/-14 -25/-16

5 mg
Placebo-Adjusted Mean Change -12/-7 -20/-11 -20/-11 -22/-13
Mean Change -20/-13 -25/-16 -29/-17 -30/-19
10 mg
Placebo-Adjusted Mean Change -16/-10 -22/-13 -25/-14 -26/-16

The antihypertensive effect of Azor was similar in patients with and without prior
antihypertensive medication use, in patients with and without diabetes, in patients
≥65 years of age and <65 years of age, and in women and men. Limited data exist in
patients ≥75 years of age.

Azor was effective in treating black patients (usually a low-renin population), and the
magnitude of blood pressure reduction in black patients approached that observed for
non-Black patients. This effect in black patients has been seen with ACE inhibitors,
angiotensin receptor blockers, and beta-blockers.

The blood pressure lowering effect was maintained throughout the 24-hour period with
Azor once daily, with trough-to-peak ratios for systolic and diastolic response between
71% and 82%.

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 Upon completing the 8-week, double-blind, placebo-controlled study, 1684 patients
entered a 44-week open-label extension and received combination therapy with
amlodipine 5 mg plus olmesartan medoxomil 40 mg. During the open-label extension,
patients whose blood pressure was not adequately controlled (i.e., did not achieve a
blood pressure goal of <140/90 mmHg, or <130/80 mmHg for those patients with
diabetes) on amlodipine/olmesartan medoxomil 5/40 mg were titrated to amlodipine
/olmesartan medoxomil 10/40 mg. Patients whose blood pressure was still not
adequately controlled were offered additional hydrochlorothiazide 12.5 mg and
subsequently 25 mg as required to achieve adequate blood pressure goal.

There are no trials of Azor demonstrating reductions in cardiovascular risk in patients with
hypertension, but at least one pharmacologically similar drug has demonstrated such
benefits.

14.2 Amlodipine
The antihypertensive efficacy of amlodipine has been demonstrated in a total of
15 double-blind, placebo-controlled, randomized studies involving 800 patients on
amlodipine and 538 on placebo. Once daily administration produced statistically
significant placebo-corrected reductions in supine and standing blood pressures at
24 hours post-dose, averaging about 12/6 mmHg in the standing position and
13/7 mmHg in the supine position in patients with mild to moderate hypertension.
Maintenance of the blood pressure effect over the 24-hour dosing interval was
observed, with little difference in peak and trough effect.

14.3 Olmesartan Medoxomil

The antihypertensive effects of olmesartan medoxomil have been demonstrated in
seven placebo-controlled studies at doses ranging from 2.5 mg to 80 mg for 6 to
12 weeks, each showing statistically significant reductions in peak and trough blood
pressure. A total of 2693 patients (2145 olmesartan medoxomil; 548 placebo) with
essential hypertension were studied. The blood pressure lowering effect was
maintained throughout the 24-hour period with olmesartan medoxomil once daily, with
trough-to-peak ratios for systolic and diastolic response between 60% and 80%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Azor tablets contain amlodipine besylate at a dose equivalent to 5 or 10 mg amlodipine
and olmesartan medoxomil in the strengths described below.

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 Azor tablets are differentiated by tablet color/size and are debossed with an individual
product tablet code on one side. Azor tablets are supplied for oral administration in the
following strength and package configurations:

Tablet Strength
(amlodipine
equivalent/
olmesartan Package Product Tablet
medoxomil) mg Configuration NDC# Code Color
5/20 mg Bottle of 30 65597-110-30 C73 White
Bottle of 90 65597-110-90
10 blisters of 10 65597-110-10
Bottle of 1000 65597-110-11
10/20 mg Bottle of 30 65597-111-30 C74 Grayish
Bottle of 90 65597-111-90 Orange
10 blisters of 10 65597-111-10
Bottle of 1000 65597-111-11
5/40 mg Bottle of 30 65597-112-30 C75 Cream
Bottle of 90 65597-112-90
10 blisters of 10 65597-112-10
Bottle of 1000 65597-112-11
10/40 mg Bottle of 30 65597-113-30 C77 Brownish
Bottle of 90 65597-113-90 Red
10 blisters of 10 65597-113-10
Bottle of 1000 65597-113-11

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP

Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Physicians should instruct female patients of childbearing age about the consequences
of second and third trimester exposure to drugs that act on the renin-angiotensin system
and they should be told that these consequences do not appear to have resulted from
intrauterine drug exposure that has been limited to the first trimester. These patients
should be informed to report pregnancies to their physicians as soon as possible. [See
Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

Manufactured for Daiichi Sankyo, Inc., Parsippany, New Jersey 07054

Manufactured by Daiichi Sankyo Europe GmbH, Germany

Copyright © Daiichi Sankyo, Inc. 2007. All rights reserved.

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