1 INDICATIONS AND USAGE Olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets are indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and myocardial infarctions.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs.

There are no controlled trials demonstrating risk reduction with olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

Many patients will require more than one drug to achieve blood pressure goals.

For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits.

The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.

Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).

These considerations may guide selection of therapy.

Limitations of Use This fixed combination drug is not indicated for the initial therapy of hypertension.

Olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets is a combination of an angiotensin II receptor blocker, a dihydropyridine calcium channel blocker, and a thiazide diuretic indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

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Limitations of Use Olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets are not indicated for initial therapy.

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6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥2%) are dizziness, peripheral edema, headache, fatigue, nasopharyngitis, muscle spasms, nausea, upper respiratory tract infection, diarrhea, urinary tract infection, and joint swelling ( 6.1 ).

To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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.

Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide In the controlled trial of olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets, patients were randomized to olmesartan medoxomil/amlodipine/hydrochlorothiazide tablets 40/10/25 mg, olmesartan medoxomil/amlodipine 40/10 mg, olmesartan medoxomil/hydrochlorothiazide 40/25 mg, or amlodipine/hydrochlorothiazide 10/25 mg.

Subjects who received triple combination therapy were treated between two and four weeks with one of the three dual combination therapies.

Safety data from this study were obtained in 574 patients with hypertension who received olmesartan medoxomil, amlodipine and hydrochlorothiazide for 8 weeks.

The frequency of adverse reactions was similar between men and women, patients <65 years of age and patients ≥65 years of age, patients with and without diabetes, and Black and non-Black patients.

Discontinuations because of adverse events occurred in 4% of patients treated with olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets 40/10/25 mg compared to 1% of patients treated with olmesartan medoxomil/amlodipine 40/10 mg, 2% of patients treated with olmesartan medoxomil/hydrochlorothiazide 40/25 mg, and 2% of patients treated with amlodipine/hydrochlorothiazide 10/25 mg.

The most common reason for discontinuation with olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets was dizziness (1%).

Dizziness was one of the most frequently reported adverse reactions with incidence of 1.4% to 3.6% in subjects continuing on dual combination therapy compared to 5.8% to 8.9% in subjects who switched to olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets.

The other most frequent adverse reactions that occurred in at least 2% of subjects are presented in the table below: Table 1 Adverse Reaction OM40/ AML10/ HCTZ25 mg (N = 574) n (%) OM40/ AML10 mg (N = 596) n (%) OM40/ HCTZ25mg (N = 580) n (%) AML10/ HCTZ25 mg (N = 552) n (%) Edema peripheral 44 (7.7) 42 (7.0) 6 (1.0) 46 (8.3) Headache 37 (6.4) 42 (7.0) 38 (6.6) 33 (6.0) Fatigue 24 (4.2) 34 (5.7) 31 (5.3) 36 (6.5) Nasopharyngitis 20 (3.5) 11 (1.8) 20 (3.4) 16 (2.9) Muscle spasms 18 (3.1) 12 (2.0) 14 (2.4) 13 (2.4) Nausea 17 (3.0) 12 (2.0) 22 (3.8) 12 (2.2) Upper respiratory tract infection 16 (2.8) 26 (4.4) 18 (3.1) 14 (2.5) Diarrhea 15 (2.6) 14 (2.3) 12 (2.1) 9 (1.6) Urinary tract infection 14 (2.4) 8 (1.3) 6 (1.0) 7 (1.3) Joint swelling 12 (2.1) 17 (2.9) 2 (0.3) 16 (2.9) Syncope was reported by 1% of olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets subjects compared to 0.5% or less for the other treatment groups.

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 reactions similar to that seen with placebo.

Adverse reactions were generally mild, transient, and without relationship to the dose of olmesartan medoxomil.

Amlodipine Amlodipine has been evaluated for safety in more than 11,000 patients in U.S.

and foreign clinical trials.

6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of the individual components of olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets.

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.

Olmesartan medoxomil.

The following adverse reactions have been reported in post-marketing experience: Body as a Whole: asthenia, angioedema, anaphylactic reactions, peripheral edema Gastrointestinal: vomiting, diarrhea, spruce-like enteropathy [ see Warnings and Precautions ( 5.10 )] Metabolic and Nutritional Disorders: hyperkalemia Musculoskeletal: rhabdomyolysis Urogenital System: acute renal failure, increased blood creatinine Skin and Appendages: alopecia, pruritus, urticaria Data from one controlled trial and an epidemiologic study have suggested that high-dose olmesartan may increase cardiovascular (CV) risk in diabetic patients, but the overall data are not conclusive.

The randomized, placebo-controlled, double-blind ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention trial, n= 4447) examined the use of olmesartan, 40 mg daily, vs.

placebo in patients with type 2 diabetes mellitus, normoalbuminuria, and at least one additional risk factor for CV disease.

The trial met its primary endpoint, delayed onset of microalbuminuria, but olmesartan had no beneficial effect on decline in glomerular filtration rate (GFR).

There was a finding of increased CV mortality (adjudicated sudden cardiac death, fatal myocardial infarction, fatal stroke, revascularization death) in the olmesartan group compared to the placebo group (15 olmesartan vs.

3 placebo, HR 4.9, 95% confidence interval [CI], 1.4, 17), but the risk of non-fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35, 1.18).

The epidemiologic study included patients 65 years and older with overall exposure of >300,000 patient-years.

In the sub-group of diabetic patients receiving high-dose olmesartan (40 mg/d) for > 6 months, there appeared to be an increased risk of death (HR 2.0, 95% CI 1.1, 3.8) compared to similar patients taking other angiotensin receptor blockers.

In contrast, high-dose olmesartan use in non-diabetic patients appeared to be associated with a decreased risk of death (HR 0.46, 95% CI 0.24, 0.86) compared to similar patients taking other angiotensin receptor blockers.

No differences were observed between the groups receiving lower doses of olmesartan compared to other angiotensin blockers or those receiving therapy for ˂6 months.

Overall, these data raise a concern of a possible increased CV risk associated with the use of high-dose olmesartan in diabetic patients.

There are, however, concerns with the credibility of the finding of increased CV risk, notably the observation in the large epidemiologic study for a survival benefit in non-diabetics of a magnitude similar to the adverse finding in diabetics.

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.

Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine.

Hydrochlorothiazide .

Non-melanoma Skin Cancer Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer.

In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses.

The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.