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
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 |
* 12.3%=actual placebo incidence
|
| | Olmesartan Medoxomil |
| | Placebo | 20 mg | 40 mg |
| Amlodipine | Placebo | ļ¼%* | -2.4% | 6.2% |
| 5mg | 0.7% | 5.7% | 6.2% |
| 10 mg | 24.5% | 13.3% | 11.2% |
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 |
* 1Hypertension is counted as treatment failure and not as treatment emergent adverse event.
N=160-163 subjects per treatment group.
|
| | 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% |
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%).
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
Gastrointestinal: vomiting
Musculoskeletal: rhabdomyolysis
Urogenital System: acute renal failure
Skin and Appendages: alopecia, pruritus, urticaria
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