Amlodipine and Olmesartan Medoxomil (Page 2 of 7)

5.3 Increased Angina or Myocardial Infarction

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.

5.4 Impaired Renal Function

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 patients treated with amlodipine and olmesartan medoxomil because of the olmesartan medoxomil component [see Drug Interactions (7) and 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 amlodipine and olmesartan medoxomil.

5.5 Patients with 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 amlodipine and olmesartan medoxomil is 5/20 mg; therefore, initial therapy with amlodipine and olmesartan medoxomil is not recommended in hepatically impaired patients [see Use in Specific Populations (8.6)].

Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t_½ ) is 56 hours in patients with severely impaired hepatic function, titrate slowly when administering to patients with severe hepatic impairment.

5.6 Sprue-like Enteropathy

Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of amlodipine and olmesartan medoxomil in cases where no other etiology is identified.

5.7 Electrolyte Imbalances

Amlodipine and olmesartan medoxomil contains olmesartan, a drug that inhibits the renin-angiotensin system (RAS). Drugs that inhibit the RAS can cause hyperkalemia. Monitor serum electrolytes periodically.

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.

Amlodipine and Olmesartan Medoxomil

The data described below reflect exposure to amlodipine and olmesartan medoxomil in more than 1600 patients including more than 1000 exposed for at least 6 months and more than 700 exposed for 1 year. Amlodipine and olmesartan medoxomil was studied in one placebo-controlled factorial trial [se e Clinical Trials (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 amlodipine and olmesartan medoxomil was similar to that seen with corresponding doses of the individual components of amlodipine and olmesartan medoxomil, and to placebo. The reported adverse reactions were generally mild and seldom led to discontinuation of treatment (2.6% for amlodipine and olmesartan medoxomil 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	－*	-2.4%	6.2%
	5 mg	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.
There was a greater decrease in hemoglobin and hematocrit in patients treated with amlodipine and olmesartan medoxomil as compared to patients receiving either component.

Adverse reactions seen at lower rates during the double-blind period also occurred in the patients treated with amlodipine and olmesartan medoxomil 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 amlodipine and olmesartan medoxomil caused slightly more hypotension and orthostatic symptoms, but not at the recommended starting dose of amlodipine and olmesartan medoxomil 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

1 Hypertension is counted as treatment failure and not as treatment emergent adverse event.N=160 to 163 subjects per treatment group.
		Olmesartan Medoxomil
		Placebo	10 mg	20 mg	40 mg
Amlodipine	Placebo	4.9%	4.3%	5.6%	3.1%
	5 mg	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	PlaceboN=520	2.5 mgN=275	5 mgN=296	10 mgN=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 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%).