Amlodipine besylate and Olmesartran medoxomil 10 mg; 40 mg Tablet, Film Coated, 1,000-count

5 WARNINGS AND PRECAUTIONS · Hypotension in volume-or salt-depleted patients with treatment initiation may be anticipated. Start treatment under close supervision (5.2). · Increased angina or myocardial infarction may occur upon dosage initiation or increase (5.3). · Impaired renal function: changes in renal function may be anticipated in susceptible individual (5.4). · Sprue-like enteropathy has been reported. Consider discontinuation of amlodipine and olmesartan medoxomil tablets in cases where no other etiology is found (5.6).

5.1Fetal Toxicity Pregnancy Category D 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 [see Use in specific Populations (8.1].

5.2Hypotension 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.

5.3Increased Angina or Myocardial Infraction Amlodipine. Since the vasodilation attributable to amlodipine in amlodipine and olmesartan medoxomil tablets is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, exercise caution, as with any other peripheral vasodilator, when administering amlodipine and olmesartan medoxomil tablets, particularly in patients with severe aortic stenosis.

5.4Patients with Impaired Renal Function 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 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 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 tablets.

5.5Patients 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 are 5/20 mg; therefore, initial therapy with…

6 ADVERSE REACTIONS Most common adverse reaction (incidence ≥3%) is edema (6.1). To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-332-1088 or www.fda.gov/medwatch.

6.1Clinical 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 1000 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 were 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 Amlodipine Placebo －* -2.4% 6.2% 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 tablets 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 Amlodipine Placebo 4.9% 4.3% 5.6% 3.1% 5 mg 3.7% 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…

7 DRUG INTERACTIONS Amlodipine (7.1): • If simvastatin is co-administered with amlodipine, do not exceed doses greater than 20 mg daily of simvastatin. • Increased exposure of cyclosporin and tacrolimus. • Increased exposure of amlodipine when coadminstred with CYP3A inhibitors. Olmesartan medoxomil (7.2): Nonsteroidal anti-inflammatory drugs (NSAIDS) may lead to increased risk of renal impairment and loss of antihypertensive effect. Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia.

Colesevelam hydrochloride: Consider administering olmesartan at least 4 hours before colesevelam hydrochloride dose. Lithium: Increases in serum lithium concentrations and lithium toxicity.

7.1Drug Interactions with Amlodipine Simvastatin: Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily [see Clinical Pharmacology (12.3)] . Immunosuppressants: Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered.

Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology (12.3)] . CYP3A Inhibitors: Co-administration of amlodipine with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment .

CYP3A Inducers: No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers.

7.2Drug Interactions with Olmesartan Medoxomil 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 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. Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.

Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on amlodipine and olmesartan medoxomil tablets and other agents that affect the RAS.

Do not co-administer aliskiren with amlodipine and olmesartan medoxomil tablets in patients with diabetes [see Contraindications (4 ) ] . Avoid use of aliskiren with amlodipine and olmesartan medoxomil tablets in patients with renal impairment (GFR <60 ml/min). Use with Colesevelam Hydrochloride Concurrent administration of bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan.

Administration of olmesartan at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose [see Clinical Pharmacology (12.3)] . Lithium Increases in serum lithium concentrations a…