1INDICATIONS AND USAGE Valsartan tablets are angiotensin II receptor blocker (ARB) indicated for: Hypertension, to lower blood pressure in adults and children 6 years and older.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1.1) Heart failure (NYHA class II-IV), to reduce hospitalization for heart failure in adults (1.2) Post-myocardial infarction, for the reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction in adults( 1.3 ) 1.1 Hypertension Valsartan tablets are indicated for the treatment of hypertension, to lower blood pressure in adults and pediatric patients six years of age and older.

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 the class to which valsartan principally belongs.

There are no controlled trials in hypertensive patients demonstrating risk reduction with 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 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 (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.

Valsartan tablets may be used alone or in combination with other antihypertensive agents.

Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's Diovan (valsartan) tablets.

However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

1.2 Heart Failure Valsartan tablets are indicated to reduce the risk of hospitalization for heart failure in adult patients with heart failure (NYHA class II-IV).

There is no evidence that valsartan tablets provide added benefits when it is used with an adequate dose of an angiotensin converting enzyme (ACE) inhibitor [see Clinical Studies (14.2) ].

1.3 Post-Myocardial Infarction In clinically stable adult patients with left ventricular failure or left ventricular dysfunction following myocardial infarction, Valsartan tablets is indicated to reduce the risk of cardiovascular mortality [see Clinical Studies (14.3) ].

6 ADVERSE REACTIONS Hypertension: Most common adverse reactions are headache, dizziness, viral infection, fatigue and abdominal pain ( 6.1 ) Heart Failure: Most common adverse reactions are dizziness, hypotension, diarrhea, arthralgia, back pain, fatigue and hyperkalemia ( 6.1 ) Post-Myocardial Infarction: Most common adverse reactions which caused patients to discontinue therapy are hypotension, cough and increased blood creatinine (6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Jubilant Cadista Pharmaceuticals Inc.

at 1-800-313-4623 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.

Adult Hypertension Valsartan has been evaluated for safety in more than 4,000 patients, including over 400 treated for over 6 months, and more than 160 for over 1 year.

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

The overall incidence of adverse reactions with valsartan was similar to placebo.

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

Discontinuation of therapy due to side effects was required in 2.3% of valsartan patients and 2.0% of placebo patients.

The most common reasons for discontinuation of therapy with valsartan were headache and dizziness.

The adverse reactions that occurred in placebo-controlled clinical trials in at least 1% of patients treated with valsartan and at a higher incidence in valsartan (n=2,316) than placebo (n=888) patients included viral infection (3% vs.

2%), fatigue (2% vs.

1%), and abdominal pain (2% vs.

1%).

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).

Dose-related orthostatic effects were seen in less than 1% of patients.

An increase in the incidence of dizziness was observed in patients treated with valsartan 320 mg (8%) compared to 10 to 160 mg (2% to 4%).

Pediatric Hypertension Valsartan has been evaluated for safety in over 400 patients aged 6 to 17 years.

No relevant differences were identified between the adverse experience profile for pediatric patients and that previously reported for adult patients.

Hyperkalemia was more frequently observed in pediatric patients with underlying chronic kidney disease (CKD).

Heart Failure In the Valsartan Heart Failure Trial (Val-HeFT), comparing valsartan in total daily doses up to 320 mg (n=2,506) to placebo (n=2,494), 10% of valsartan patients discontinued for adverse reactions vs.

7% of placebo patients.

The table shows adverse reactions in double-blind short-term heart failure trials, including the first 4 months of the Valsartan Heart Failure Trial, with an incidence of at least 2% that were more frequent in valsartan-treated patients than in placebo-treated patients.

All patients received standard drug therapy for heart failure, frequently as multiple medications, which could include diuretics, digitalis, beta-blockers.

About 93% of patients received concomitant ACE inhibitors.

Valsartan (n=3,282) Placebo (n=2,740) Dizziness 17% 9% Hypotension 7% 2% Diarrhea 5% 4% Arthralgia 3% 2% Fatigue 3% 2% Back Pain 3% 2% Dizziness, postural 2% 1% Hyperkalemia 2% 1% Hypotension, postural 2% 1% Discontinuations occurred in 0.5% of valsartan-treated patients and 0.1% of placebo patients for each of the following: elevations in creatinine and elevations in potassium.

Other adverse reactions with an incidence greater than 1% and greater than placebo included headache, nausea, renal impairment, syncope, blurred vision, upper abdominal pain and vertigo.

From the long-term data in the Valsartan Heart Failure Trial, there did not appear to be any significant adverse reactions not previously identified.

Post-Myocardial Infarction The table shows the percentage of patients discontinued in the valsartan and captopril-treated groups in the VALsartan In Acute myocardial iNfarcTion trial (VALIANT) with a rate of at least 0.5% in either of the treatment groups.

Discontinuations due to renal dysfunction occurred in 1.1% of valsartan-treated patients and 0.8% of captopril-treated patients.

Valsartan (n=4,885) Captopril (n=4,879) Discontinuation for adverse reaction 5.8% 7.7% Adverse reactions Hypotension NOS 1.4% 0.8% Cough 0.6% 2.5% Blood creatinine increased 0.6% 0.4% Rash NOS 0.2% 0.6% Clinical Laboratory Test Findings Creatinine: In heart failure trials, 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.

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

Blood Urea Nitrogen (BUN): In heart failure trials, 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 (5.3)] Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Diovan (valsartan) tablets.

However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that information.

6.2 Postmarketing Experience The following additional adverse reactions have been reported in postmarketing use of valsartan.

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.

Hypersensitivity: Angioedema has been reported.

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

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

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