Amlodipine and Olmesartan Medoxomil (Page 2 of 7)

4 CONTRAINDICATIONS

Do not co-administer aliskiren with amlodipine and olmesartan medoxomil tablets in patients with diabetes [s ee Drug Interactions ( 7.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

Amlodipine and olmesartan medoxomil tablets can cause fetal harm when administered to a pregnant women.Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue amlodipine and olmesartan medoxomil tablets as soon as possible [s ee Use in Specific Populations ( 8.1)].

5.2 Hypotension in Volume- or Salt-Depleted Patients

Olmesartan medoxomil. In patients with an activated renin-angiotensin system, such as volume-and/or salt-depleted patients (e.g., those being treated with high doses of diuretics) symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil.

Initiate treatment with amlodipine and olmesartan medoxomil tablets 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.

Amlodipine. Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.

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 Patients with 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 rennin-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 tablets 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 longterm 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 tablets.

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 tablets is 5/20 mg; therefore, initial therapy with amlodipine and olmesartan medoxomil tablets 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 (t½) 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 tablets in cases where no other etiology is identified.

5.7 Electrolyte Imbalances

amlodipine and olmesartan medoxomil tablets 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 Tablets

The data described below reflect exposure to amlodipine and olmesartan medoxomil tablets in more than 1600 patients including more than 1,000 exposed for at least 6 months and more than 700 exposed for 1 year. Amlodipine and olmesartan medoxomil tablets were studied in one placebo-controlled factorial trial [see 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 tablets was similar to that seen with corresponding doses of the individual components of amlodipine and olmesartan medoxomil tablets, and to placebo. The reported adverse reactions were generally mild and seldom led to discontinuation of treatment (2.6% for amlodipine and olmesartan medoxomil tablets 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.

There was a greater decrease in hemoglobin and hematocrit in patients treated with amlodipine and olmesartan medoxomil tablets 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 tablets 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 tablet caused slightly more hypotension and orthostatic symptoms, but not at the recommended starting dose of amlodipine and olmesartan medoxomil tablets 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 Event 1
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 to 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=1,730) 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 3,825 patients/subjects, including more than 3,275 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., 79/3,278) of patients treated with olmesartan medoxomil and 2.7% (i.e., 32/1,179) 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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