ADVERSE REACTIONS
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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
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
|
|
Amlodipine
|
Placebo
|
–%*
|
-2.4% |
6.2% |
|
5mg
|
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
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
|
|
Amlodipine
|
Placebo
|
4.9% |
4.3% |
5.6% |
3.1% |
|
5mg
|
3.7% |
0.0% |
1.2% |
3.7% |
|
10 mg
|
5.5% |
6.8% |
2.5% |
5.6% |
*
1Hypertension 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:
|
Adverse Event
|
Placebo
N=520
|
2.5 mg
N=275
|
5.0 mg
N=296
|
10.0 mg
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=%
(N=914)
|
Female=%
(N=336)
|
Male=%
(N=1218)
|
Female=%
(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 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%).
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
Gastrointestinal:
vomiting
Musculoskeletal:
rhabdomyolysis
Urogenital System: acute
renal failure
Skin and Appendages:
alopecia, pruritus, urticaria
|
