Valsartan

1 INDICATIONS AND USAGE Valsartan tablets are an angiotensin II receptor blocker (ARB) indicated for: Hypertension ,to lower blood pressure. 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); valsartan tablets significantly reduced hospitalization for heart failure ( 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 ( 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 patients with heart failure (NYHA class II-IV). There is no evidence that valsartan tablets provide added benefits when they are used with an adequate dose of an ACE inhibitor [See Clinical Studies (14.2) ] . 1.3 Post-Myocardial Infarction In clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction, valsartan tablets are indicated to reduce the risk of cardiovascular mortality [See Clinical Studies (14.3) ] .

2 DOSAGE AND ADMINISTRATION Indication Starting Dose Dose Range * Adult Hypertension ( 2.2 ) 80 or 160 mg once daily 80-320 mg once daily 6-16 years ( 2.3 ) 1mg/kg once daily (up to 40 mg total) 1-4mg/kg once daily (up to 160 mg total) Heart Failure ( 2.4 ) 40 mg twice daily 40-160 mg twice daily Post-Myocardial Infarction ( 2.5 ) 20 mg twice daily 20-160 mg twice daily * As tolerated by patient 2.1 Important Dosage and Preparation Information Valsartan tablets and oral suspension are not substitutable on a milligram-per-milligram basis. Do not combine two dosage forms to achieve the total dose. The systemic exposure to valsartan (AUC) is 60% higher with the suspension compared to tablets [ S ee Clinical Pharmacology (12.3) ] . Use of the oral suspension is recommended: in patients ≥ 6 years of age who cannot swallow tablets and in pediatric patients for whom the calculated dose (mg/kg) does not correspond to the available tablet strengths of valsartan tablets When switching between suspension and tablets, the dose of valsartan may need to be adjusted. Preparation of Suspension (for 160 mL of a 4 mg/mL suspension) Add 80 mL of Ora-Plus ® * oral suspending vehicle to an amber glass bottle containing 8 valsartan 80 mg tablets and shake for a minimum of 2 minutes. Allow the suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a minimum of 1 additional minute. Add 80 mL of Ora-Sweet SF ® * oral sweetening vehicle to the bottle and shake the suspension for at least 10 seconds to disperse the ingredients. The suspension is homogenous and can be stored for either up to 30 days at room temperature (below 30°C/86°F) or up to 75 days at refrigerated conditions (2°C to 8°C/35°F to 46°F) in the glass bottle with a child-resistant screw-cap closure. Shake the bottle well (at least 10 seconds) prior to dispensing the suspension *Ora-Sweet SF ® and Ora-Plus ® are registered trademarks of Paddock Laboratories, Inc. 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 2.2 Adult Hypertension The recommended starting dose of valsartan tablets is 80 mg or 160 mg once daily when used as monotherapy in patients who are not volume-depleted. Patients requiring greater reductions may be started at the higher dose. Valsartan tablets may be used over a dose range of 80 mg to 320 mg daily, administered once a day. The antihypertensive effect is substantially present within 2 weeks and maximal reduction is generally attained after 4 weeks. If additional antihypertensive effect is required over the starting dose range, the dose may be increased to a maximum of 320 mg or a diuretic may be added. Addition of a diuretic has a greater effect than dose increases beyond 80 mg. Valsartan tablets may be administered with other antihypertensive agents. 2.3 Pediatric Hypertension 6 to 16 Years of Age The usual recommended starting dose is 1 mg/kg once daily (up to 40 mg total). A higher starting dose of 2 mg/kg may be considered in selected cases when a greater reduction of blood pressure is needed. The dosage should be adjusted according to blood pressure response and tolerability, up to a maximum dose of 4 mg/kg once daily (maximum daily dose 160 mg). No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate <30 mL/min/1.73 m2 [ S ee Use in Specific Populations (8.4 ) ] . Use of valsartan tablets are not recommended in children less than 1 year of age [ S ee Adverse Reactions (6.1) , Pediatric Use in Specific Populations (8.4) , Nonclinical Toxicology (13.2) ]. 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. 2.4 Heart Failure The recommended starting dose of valsartan tablets is 40 mg twice daily. Uptitrate to 80 mg and 160 mg twice daily or to the highest dose tolerated by the patient. Consider reducing the dose of concomitant diuretics. The maximum daily dose administered in clinical trials is 320 mg in divided doses. 2.5 Post-Myocardial Infarction Valsartan tablets may be initiated as early as 12 hours after a myocardial infarction. The recommended starting dose of valsartan tablets is 20 mg twice daily. Patients may be uptitrated within 7 days to 40 mg twice daily, with subsequent titrations to a target maintenance dose of 160 mg twice daily, as tolerated by the patient. If symptomatic hypotension or renal dysfunction occurs, consider dosage reduction. Valsartan tablets may be given with other standard post-myocardial infarction treatment, including thrombolytics, aspirin, beta-blockers, and statins. 2.6 Missed Dose If a dose of valsartan tablets are missed, it should be administered as soon as possible, unless it is almost time for the next dose. The dose should not be doubled to make up for a missed dose.

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 RK Pharma Inc at 1-844-757-4276 (1-844-RKPHARMA) 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 tablets have 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 tablets 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 tablets were headache and dizziness. The adverse reactions that occurred in placebo-controlled clinical trials in at least 1% of patients treated with valsartan tablets 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 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 tablets 320 mg (8%) compared to 10 to 160 mg (2% to 4%). Pediatric Hypertension Valsartan tablets have 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 tablet-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 tablets 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 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. Hypersensitivity : Angioedema has been reported. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Valsartan tablets should not be re-administered to patients who have had angioedema. Digestiv e : 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

12.3 Pharmacokinetics Absorption In healthy volunteers, valsartan peak plasma concentration is reached 2 to 4 hours after dosing. Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours. Absolute bioavailability for valsartan tablets is about 25% (range 10% to 35%). The bioavailability of the suspension [See Dosage and Administration (2.2) ] is 1.6 times as great as with the tablet. AUC and C max values of valsartan increase approximately linearly with increasing dose over the clinical dosing range (80-320 mg). Valsartan does not accumulate appreciably in plasma following repeated administration of 200 mg once daily. In heart failure patients, the average time to peak plasma concentration and elimination half-life of valsartan are similar to those observed in healthy volunteers. The average accumulation factor is about 1.7 in heart failure patients following repeated administration of 160 mg twice daily. AUC and C max values of valsartan increase linearly and are almost proportional with increasing dose from 40 to 160 mg twice a day. Effect of Food With the tablet, food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (C max ) by about 50%. Valsartan tablets can be administered with or without food. Distribution The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin. Metabolism The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. Excretion Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance). The apparent clearance of valsartan following oral administration is approximately 4.5 L/h in heart failure patients. Age does not affect the apparent clearance in heart failure patients. Specific Populations Geriatric Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young [See Use in Specific Populations (8.5) ] . Pediatric In a study of pediatric hypertensive patients (n=26, 1 to 16 years of age) given single doses of a suspension of Valsartan tablets (mean: 0.9 to 2 mg/kg), the clearance (L/h/kg) of valsartan for children was similar to that of adults receiving the same formulation. Valsartan pharmacokinetics have not been investigated in pediatric patients less than 1 year of age. Gender Pharmacokinetics of valsartan does not differ significantly between males and females. Renal Insufficiency There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment (down to creatinine clearance of 10 mL/min). Valsartan is not removed from the plasma by hemodialysis [See Use in Specific Populations (8.6) ] . Hepatic Insufficiency On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex, and weight) [See Use in Specific Populations (8.7) ] . Drug Interaction Studies No clinically significant pharmacokinetic interactions were observed when valsartan tablets were coadministered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone. Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin. Transporters The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Coadministration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.