Valsartan

Diovan is an angiotensin II receptor blocker (ARB) indicated for: Hypertension , to lower blood pressure in adults and children 1 year 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 Diovan ® is indicated for the treatment of hypertension, to lower blood pressure in adults and pediatric patients one year 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 Diovan. 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. Diovan may be used alone or in combination with other antihypertensive agents.

1.2 Heart Failure Diovan is 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 Diovan provides 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, Diovan is indicated to reduce the risk of cardiovascular mortality [see Clinical Studies (14.3)] .

40 mg are functionally scored yellow ovaloid tablets with beveled edges, imprinted NVR/DO (Side 1/Side 2) 40 mg are yellow, ovaloid film-coated tablets with beveled edges, slightly convex, functionally scored on one side, with debossing “D” on one side and “O” on the other side of the score and “NVR” on the reverse side of the tablet 80 mg are pale red almond-shaped tablets with beveled edges, imprinted NVR/DV 80 mg are pale red round film-coated tablets with beveled edges, scored on one side with debossing “D” on one side and “V” on the other side of the score and “NVR” on the reverse side of the tablet 160 mg are grey-orange almond-shaped tablets with beveled edges, imprinted NVR/DX 160 mg are grey-orange ovaloid film-coated tablets, slightly convex, scored on one side with debossing “DX” on one side of the score and “DX” on the other side of the score “NVR” on the reverse side of the tablet 320 mg are dark grey-violet almond-shaped tablets with beveled edges, imprinted NVR/DXL 320 mg are dark grey-violet ovaloid film-coated tablets with beveled edges, slightly convex, scored on one side with debossing “DC” on one side of the score and “DC” on the other side of the score and “NVR” on the reverse side of the tablet Tablets: 40 mg (functional score), 80 mg, 160 mg, 320 mg

Do not use in patients with known hypersensitivity to any component. Do not coadminister aliskiren with Diovan in patients with diabetes [see Drug Interactions (7.3)] . Known hypersensitivity to any component. Do not coadminister aliskiren with Diovan in patients with diabetes ( 4 )

Observe for signs and symptoms of hypotension ( 5.2 ) Monitor renal function and potassium in susceptible patients ( 5.3 , 5.4 )

5.1 Fetal Toxicity Diovan can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Diovan as soon as possible [see Use in Specific Populations (8.1)] .

5.2 Hypotension Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with Diovan alone. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of Diovan, or the treatment should start under close medical supervision. Patients with heart failure or post-myocardial infarction patients given Diovan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. In the VALsartan In Acute myocardial iNfarcTion trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients. If excessive hypotension occurs, place the patient in the supine position and, if necessary, give intravenous normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

5.3 Impaired Renal Function Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on Diovan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Diovan [see Drug Interactions (7)] .

5.4 Hyperkalemia Some patients with heart failure have developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of Diovan may be required [see Adverse Reactions (6.1)] .

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 Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 Diovan has been evaluated for safety in more than 4000 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 Diovan 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 Diovan were headache and dizziness. The adverse reactions that occurred in placebo-controlled clinical trials in at least 1% of patients treated with Diovan and at a higher incidence in valsartan (n = 2316) 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 Diovan 320 mg (8%) compared to 10 mg to 160 mg (2% to 4%). Pediatric Hypertension Diovan has been evaluated for safety in 290 pediatric patients aged 1 to less than 6 years and 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 aged 1 to 17 years with underlying chronic kidney disease (CKD). Cases of elevated ALT and/or AST have been reported in pediatric patients 1 to less than 6 years of age. These events occurred in a study population which frequently had significant comorbidities; hence, a causal relationship to valsartan could not be established. Heart Failure In the Valsartan Heart Failure Trial (Val-HeFT), comparing valsartan in total daily doses up to 320 mg (n = 2506) to placebo (n = 2494), 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 = 3282) Placebo (n = 2740) 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 = 4885) Captopril (n = 4879) 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 Diovan-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 Diovan 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 Diovan-treated patients compared to 6.3% of placebo-treated patients [see Warnings and Precautions (5.3)] .

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

Potassium-sparing diuretics, potassium supplements or salt substitutes may lead to increases in serum potassium, and in heart failure patients, increases in serum creatinine ( 7.1 ) Non-Steroidal Anti-Inflammatory Drug (NSAID) use may lead to increased risk of renal impairment and loss of antihypertensive effect ( 7.2 ) Dual inhibition of the Renin-Angiotensin System (RAS): Increased risk of renal impairment, hypotension, and hyperkalemia ( 7.3 ) Lithium: Increases in serum lithium level and lithium toxicity ( 7.4 )

7.1 Agents Increasing Serum Potassium Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g., heparin) may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If co-medication is considered necessary, monitoring of serum potassium is advisable.

7.2 Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving valsartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including valsartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors.

7.3 Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy [see Clinical Studies (14.3)] . In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Diovan and other agents that affect the RAS. Do not coadminister aliskiren with Diovan in patients with diabetes. Avoid use of aliskiren with Diovan in patients with renal impairment (GFR < 60 mL/min).

7.4 Lithium Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use.

Lactation: Breastfeeding is not recommended ( 8.2 ) Pediatrics: Use of Diovan is not recommended in children less than 1 year of age ( 6.1 , 8.4 , 13.2 )

8.1 Pregnancy Risk Summary Diovan can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Published reports include cases of anhydramnios and oligohydramnios in pregnant women treated with valsartan (see Clinical Considerations) . When pregnancy is detected, consider alternative drug treatment and discontinue Diovan as soon as possible. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. In patients taking Diovan during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, consider alternative drug treatment. Closely observe neonates with histories of in utero exposure to Diovan for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to Diovan, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function. Data Animal Data No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses of up to 600 mg/kg/day (9 and 18 times the maximum recommended human dose (MRHD) on a mg/m 2 basis) and to pregnant rabbits at oral doses of up to 10 mg/kg/day. In rats, oral valsartan administered at maternally toxic doses (600 mg/kg/day) during organogenesis or late gestation and lactation, resulted in decreased fetal and pup weight, pup survival and delayed developmental milestones. In rabbits administered maternally toxic doses of 5 mg/kg/day and 10 mg/kg/day, fetotoxicity was observed.

8.2 Lactation Risk Summary There is no information regarding the presence of Diovan in human milk, the effects on the breastfed infant, or the effects on milk production. Diovan is present in rat milk. Because of the potential for serious adverse reactions in breastfed infants from exposure to valsartan, advise a nursing woman that breastfeeding is not recommended during treatment with Diovan. Data Valsartan was detected in the milk of lactating rats 15 minutes after oral administration of a 3 mg/kg dose.

8.4 Pediatric Use The antihypertensive effects of Diovan have been evaluated in 5 clinical studies in pediatric patients from 1-16 years of age [see Clinical Studies (14.1)]. The pharmacokinetics of Diovan have been evaluated in pediatric patients 1 to 16 years of age [see Clinical Pharmacology (12.3)] . The adverse experience profile of Diovan was similar to that described for adults [see Adverse Reactions (6.1)] . In children and adolescents with hypertension where underlying renal abnormalities may be more common, renal function and serum potassium should be closely monitored as clinically indicated. Use of Diovan is not recommended in children less than 1 year of age [see Nonclinical Toxicology (13.2)] . It is not known whether post-natal use of valsartan, before maturation of renal function is complete, has a long-term deleterious effect on the kidney. No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate less than 30 mL/min/1.73 m 2 .

8.5 Geriatric Use In the controlled clinical trials of valsartan, 1214 (36.2%) hypertensive patients treated with valsartan were ≥ 65 years and 265 (7.9%) were ≥ 75 years. No overall difference in the efficacy or safety of valsartan was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out. Exposure [measured by area under the curve (AUC)] to valsartan is higher by 70% in the elderly than in the young, however no dosage adjustment is necessary [see Clinical Pharmacology (12.3)] . Of the 2511 patients with heart failure randomized to valsartan in the Valsartan Heart Failure Trial, 45% (1,141) were 65 years of age or older. In the VALsartan In Acute myocardial iNfarcTion trial (VALIANT), 53% (2596) of the 4909 patients treated with valsartan and 51% (2515) of the 4885 patients treated with valsartan + captopril were 65 years of age or older. There were no notable differences in efficacy or safety between older and younger patients in either trial.

8.6 Renal Impairment Safety and effectiveness of Diovan in patients with severe renal impairment (glomerular filtration rate less than 30 mL/min/1.73 m 2 ) have not been established. No dose adjustment is required in patients with mild (glomerular filtration rate 60 to 90 mL/min/1.73 m 2 ) or moderate (glomerular filtration rate 30 to 60 mL/min/1.73 m 2 ) renal impairment.

8.7 Hepatic Impairment No dose adjustment is necessary for patients with mild-to-moderate liver disease. No dosing recommendations can be provided for patients with severe liver disease.

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Diovan (valsartan) blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. There is also an AT 2 receptor found in many tissues, but AT 2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT 1 receptor than for the AT 2 receptor. The increased plasma levels of angiotensin II following AT 1 receptor blockade with valsartan may stimulate the unblocked AT 2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT 1 receptor about one-200 th (1/200 th ) that of valsartan itself. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.