1 INDICATIONS AND USAGE Amlodipine and valsartan is the combination tablet of amlodipine, a dihydropyridine calcium channel blocker (DHP CCB), and valsartan, an angiotensin II receptor blocker (ARB).

Amlodipine and valsartan tablets are indicated for the treatment of hypertension, to lower blood pressure: • In patients not adequately controlled on monotherapy ( 1 ) • As initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals ( 1 ) Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

1.1 Hypertension Amlodipine and valsartan tablets are 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.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including amlodipine and the angiotensin II receptor blocker (ARB) class to which valsartan principally belongs.

There are no controlled trials demonstrating risk reduction with amlodipine and valsartan 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 1 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.

Amlodipine and valsartan tablets are indicated for the treatment of hypertension.

Amlodipine and valsartan tablets may be used in patients whose blood pressure is not adequately controlled on either monotherapy.

Amlodipine and valsartan tablets may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals.

The choice of amlodipine and valsartan tablets as initial therapy for hypertension should be based on an assessment of potential benefits and risks including whether the patient is likely to tolerate the lowest dose of amlodipine and valsartan tablets.

Patients with stage 2 hypertension (moderate or severe) are at a relatively higher risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure and vision problems, so prompt treatment is clinically relevant.

The decision to use a combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal and the incremental likelihood of achieving goal with a combination compared to monotherapy.

Individual blood pressure goals may vary based upon the patient’s risk.

Data from the high-dose multifactorial study [see Clinical Studies (14) ] provide estimates of the probability of reaching a blood pressure goal with amlodipine and valsartan tablets compared to amlodipine or valsartan monotherapy.

The figures below provide estimates of the likelihood of achieving systolic or diastolic blood pressure control with amlodipine and valsartan tablets 10/320 mg, based upon baseline systolic or diastolic blood pressure.

The curve of each treatment group was estimated by logistic regression modeling.

The estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures.

For example, a patient with a baseline blood pressure of 160/100 mmHg has about a 67% likelihood of achieving a goal of < 140 mmHg (systolic) and 80% likelihood of achieving < 90 mmHg (diastolic) on amlodipine alone, and the likelihood of achieving these goals on valsartan alone is about 47% (systolic) or 62% (diastolic).

The likelihood of achieving these goals on amlodipine and valsartan tablets rises to about 80% (systolic) or 85% (diastolic).

The likelihood of achieving these goals on placebo is about 28% (systolic) or 37% (diastolic).

Amlodipine and Valsartan Figures 01 - 04

6 ADVERSE REACTIONS In placebo-controlled clinical trials, discontinuation due to side effects occurred in 1.8% of patients in the amlodipine and valsartan tablets-treated patients and 2.1% in the placebo-treated group.

The most common reasons for discontinuation of therapy with amlodipine and valsartan tablets were peripheral edema and vertigo.

The adverse experiences that occurred in clinical trials (≥ 2% of patients) at a higher incidence than placebo included peripheral edema, nasopharyngitis, upper respiratory tract infection, and dizziness.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Studies with Amlodipine and Valsartan Tablets Amlodipine and valsartan tablets have been evaluated for safety in over 2600 patients with hypertension; over 1440 of these patients were treated for at least 6 months and over 540 of these patients were treated for at least 1 year.

Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.

The hazards [see Warnings and Precautions (5) ] of valsartan are generally independent of dose; those of amlodipine are a mixture of dose-dependent phenomena (primarily peripheral edema) and dose-independent phenomena, the former much more common than the latter.

The overall frequency of adverse reactions was neither dose-related nor related to gender, age, or race.

In placebo-controlled clinical trials, discontinuation due to side effects occurred in 1.8% of patients in the amlodipine and valsartan tablets-treated patients and 2.1% in the placebo-treated group.

The most common reasons for discontinuation of therapy with amlodipine and valsartan tablets were peripheral edema (0.4%), and vertigo (0.2%).

The adverse reactions that occurred in placebo-controlled clinical trials in at least 2% of patients treated with amlodipine and valsartan tablets but at a higher incidence in amlodipine/valsartan patients (n = 1437) than placebo (n = 337) included peripheral edema (5.4% vs 3.0%), nasopharyngitis (4.3% vs 1.8%), upper respiratory tract infection (2.9% vs 2.1%) and dizziness (2.1% vs 0.9%).

Orthostatic events (orthostatic hypotension and postural dizziness) were seen in less than 1% of patients.

Studies with Valsartan Diovan ® has been evaluated for safety in more than 4000 hypertensive patients in clinical trials.

In trials in which valsartan was compared to an angiotensin-converting enzyme (ACE) inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%).

In a 129-patient trial limited to patients who had had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p < 0.001).

Clinical Lab Test Findings Creatinine In heart failure patients, greater than 50% increases in creatinine were observed in 3.9% of valsartan-treated patients compared to 0.9% of placebo-treated patients.

In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients.

Blood Urea Nitrogen (BUN) In hypertensive patients, greater than 50% increases in BUN were observed in 5.5% of amlodipine and valsartan tablets-treated patients compared to 4.7% of placebo-treated patients.

In heart failure patients, greater than 50% increases in BUN were observed in 16.6% of valsartan-treated patients compared to 6.3% of placebo-treated patients [see Warnings and Precautions (5.4) ] .

Neutropenia Neutropenia was observed in 1.9% of patients treated with Diovan and 0.8% of patients treated with placebo.

6.2 Postmarketing Experience The following additional adverse reactions have been reported in postmarketing experience.

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 Gynecomastia has been reported infrequently and a causal relationship is uncertain.

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.

Valsartan The following additional adverse reactions have been reported in postmarketing experience with valsartan: Hypersensitivity: Angioedema has been reported.

Some of these patients previously experienced angioedema with other drugs including ACE inhibitors.

Diovan should not be re-administered to patients who have had angioedema.

Digestive: Elevated liver enzymes and reports of hepatitis Musculoskeletal : Rhabdomyolysis Renal: Impaired renal function, renal failure Dermatologic: Alopecia, bullous dermatitis Blood and Lymphatic: Thrombocytopenia Vascular: Vasculitis