1 INDICATIONS AND USAGE Amlodipine/valsartan/hydrochlorothiazide is 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, hydrochlorothiazide, and the ARB class to which valsartan principally belongs.

There are no controlled trials demonstrating risk reduction with amlodipine/valsartan/hydrochlorothiazide.

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 (e.g., 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.

Limitation of Use Amlodipine/valsartan/hydrochlorothiazide is not indicated for the initial therapy of hypertension [see Dosage and Administration (2)].

Amlodipine/valsartan/hydrochlorothiazide is a combination tablet of amlodipine, a dihydropyridine calcium channel blocker (DHP CCB), valsartan, an angiotensin II receptor blocker (ARB), and hydrochlorothiazide, a thiazide diuretic.

Amlodipine/Valsartan/Hydrochlorothiazide is 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.

(1) Limitation of Use Amlodipine/valsartan/hydrochlorothiazide is not indicated for initial treatment of hypertension.

6 ADVERSE REACTIONS Most common adverse events (≥2% incidence) are dizziness, peripheral edema, headache, dyspepsia, fatigue, muscle spasms, back pain, nausea and nasopharyngitis.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Strides Pharma Inc at 1-877-244-9825 and/or www.strides.com 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 clinical practice.

In the controlled trial of amlodipine/valsartan/hydrochlorothiazide, where only the maximum dose (10/320/25 mg) was evaluated, safety data were obtained in 582 patients with hypertension.

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

The overall frequency of adverse reactions was similar between men and women, younger (< 65 years) and older (≥ 65 years) patients, and black and white patients.

In the active controlled clinical trial, discontinuation because of adverse events occurred in 4.0% of patients treated with amlodipine/valsartan/hydrochlorothiazide 10/320/25 mg compared to 2.9% of patients treated with valsartan/HCTZ 320/25 mg, 1.6% of patients treated with amlodipine/valsartan 10/320 mg, and 3.4% of patients treated with HCTZ/amlodipine 25/10 mg.

The most common reasons for discontinuation of therapy with amlodipine/valsartan/hydrochlorothiazide were dizziness (1.0%) and hypotension (0.7%).

The most frequent adverse events that occurred in the active controlled clinical trial in at least 2% of patients treated with amlodipine/valsartan/hydrochlorothiazide are presented in the following table.

Aml/Val/HCTZ Val/HCTZ Aml/Val HCTZ/Aml Preferred Term 10/320/25 mg N=582 n (%) 320/25 mg N=559 n (%) 10/320 mg N=566 n (%) 25/10 mg N=561 n (%) Dizziness 48 ( 8.2) 40 ( 7.2) 14 ( 2.5) 23 ( 4.1) Edema 38 ( 6.5) 8 ( 1.4) 65 (11.5) 63 ( 11.2) Headache 30 (5.2) 31 (5.5) 30 (5.3) 40 (7.1) Dyspepsia 13 ( 2.2) 5 ( 0.9) 6 ( 1.1) 2 ( 0.4) Fatigue 13 ( 2.2) 15 ( 2.7) 12 ( 2.1) 8 ( 1.4) Muscle spasms 13 ( 2.2) 7 ( 1.3) 7 ( 1.2) 5 ( 0.9) Back pain 12 ( 2.1) 13 ( 2.3) 5 ( 0.9) 12 ( 2.1) Nausea 12 ( 2.1) 7 ( 1.3) 10 ( 1.8) 12 ( 2.1) Nasopharyngitis 12 (2.1) 13 (2.3) 13 (2.3) 12 (2.1) Orthostatic events (orthostatic hypotension and postural dizziness) were seen in 0.5% of patients.

Valsartan Valsartan has been evaluated for safety in more than 4000 hypertensive patients in clinical trials.

In trials in which valsartan was compared to an 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 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 Laboratory Test Findings Clinical laboratory test findings for amlodipine/valsartan/hydrochlorothiazide were obtained in a controlled trial of amlodipine/valsartan/hydrochlorothiazide administered at the maximal dose of 10/320/25 mg compared to maximal doses of dual therapies, i.e., valsartan/HCTZ 320/25 mg, amlodipine/valsartan 10/320 mg, and HCTZ/amlodipine 25/10 mg.

Findings for the components of amlodipine/valsartan/hydrochlorothiazide were obtained from other trials.

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 30% of amlodipine/valsartan/hydrochlorothiazide-treated patients compared to 29% of valsartan/HCTZ patients, 15.8% of amlodipine/valsartan patients, and 18.5% of HCTZ/amlodipine patients.

In heart failure patients, greater than 50% increases in BUN were observed in 17% of valsartan-treated patients compared to 6% of placebo-treated patients [see Warnings and Precautions (5.4)].

Neutropenia: Neutropenia (< 1500/L) was observed in 1.9% of patients treated with valsartan 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 With 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 or valsartan/hydrochlorothiazide: Blood and Lymphatic: Decrease in hemoglobin, decrease in hematocrit, neutropenia Hypersensitivity: Angioedema has been reported.

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

Amlodipine/valsartan/hydrochlorothiazide 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 Vascular: Vasculitis Nervous System: Syncope Hydrochlorothiazide The following additional adverse reactions have been reported in postmarketing experience with hydrochlorothiazide: Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma, bone marrow failure, worsening of diabetes control, hypokalemia, blood lipids increased, hyponatremia, hypomagnesemia, hypercalcemia, hypochloremic alkalosis, impotence, visual impairment.

Pathological changes in the parathyroid gland of patients with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy.

If hypercalcemia occurs, further diagnostic evaluation is necessary.

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 ≥ 50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.