Valsartan

1 INDICATIONS AND USAGE Valsartan is an angiotensin II receptor blocker (ARB) indicated for: Hypertension in adults and children six years and older, 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 oral solution significantly reduces hospitalization for heart failure in patients who are unable to swallow valsartan tablets ( 1.2 ) Stable left ventricular failure or left ventricular dysfunction following myocardial infarction; Valsartan oral solution reduces cardiovascular mortality in patients who are unable to swallow valsartan tablets ( 1.3 ) 1.1 Hypertension Valsartan is indicated for the treatment of hypertension in adults and children six years and older, 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 the class to which valsartan principally belongs. There are no controlled trials in hypertensive patients demonstrating risk reduction with valsartan. 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 may be used alone or in combination with other antihypertensive agents. 1.2 Heart Failure Valsartan oral solution is indicated for the treatment of heart failure (NYHA class II-IV) to reduce the risk of hospitalization for heart failure in patients who are unable to swallow valsartan tablets. There is no evidence that valsartan provides added benefits when it is used with an adequate dose of an ACE inhibitor [see Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) and Clinical Studies (14.2) ]. 1.3 Post-Myocardial Infarction Valsartan oral solution is indicated to reduce the risk of cardiovascular death in clinically stable patients with le …

2 DOSAGE & ADMINISTRATION Indication Starting Dose Dose Range Target M a i n t e n a n c e Dose* Hypertension- adults (2.1) 40 or 80 mg twice daily 40 -160 mg twice daily --- Hypertension - age 6 to16 years (2.2) 0.65 mg/kg twice daily (up to 40 mg total) 0.65-1.35 mg/kg twice daily (up to 40 mg-160 mg total) --- Heart Failure (2.3) 40 mg twice daily 40 mg-160 mg twice daily 160 mg twice daily Post-Myocardial Infarction (2.4) 20 mg twice daily 20 mg to 160 mg twice daily 160 mg twice daily *as tolerated by patient 2.1 General Considerations Valsartan Oral Solution is not therapeutically equivalent to the tablet formulation of Diovan. The peak concentration of valsartan with Valsartan Oral Solution is higher than with Diovan [see Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) ] . Follow dosing instructions given here. 2.2 Adult Hypertension The recommended starting dose of Valsartan Oral Solution is 40 mg or 80 mg twice daily when used as monotherapy in patients who are not volume-depleted. Patients requiring greater reductions in blood pressure may be started at 80 mg administered twice a day. Valsartan Oral Solution may be used over a total daily dose range of 80 mg to 320 mg. 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 total daily 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. No initial dosage adjustment is required for elderly patients, for patients with mild or moderate renal impairment, or for patients with mild or moderate liver insufficiency. Monitor closely patients with severe hepatic or renal impairment. Valsartan Oral Solution may be administered with other antihypertensive agents. 2.3 Pediatric Hypertension 6 to 16 Years of Age The recommended starting dose is 0.65 mg/kg twice daily (up to 40 mg total daily dose). The dosage should be adjusted according to blood pressure response. Doses higher than 1.35 mg/kg twice daily (or >160 mg total daily dose) have not been studied in pediatric patients 6 to 16 years old. No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate <30 mL/min/1.73 m 2 [see Use in Specific Populations (8.4) ]. Valsartan Oral Solution is not recommended for patients under 6 years of age [see Adverse Reactions (6.1) , Use in Specific Populations (8.4) , Clinical Studies (14.1) ]. 2.4 Heart Failure The recommended starting dose of Valsartan Oral Solution is 40 mg twice daily. Titrate to 80 mg and 160 mg twice daily, as 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 Oral Solution may be initiated as early as 12 hours after a myocardial infarction. The recommended starting dose of Valsartan Oral Solution is 20 mg twice daily. Patients may be up titrated 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 Oral Solution may be given with other standard post-myocardial infarction treatment, including thrombolytics, aspirin, beta-blockers, and statins.

3 DOSAGE FORMS AND STRENGTHS 4 mg/mL aqueous solution. Oral Solution, 4 mg/mL ( 3 )

4 CONTRAINDICATIONS Do not use in patients with known hypersensitivity to any component. Do not coadminister aliskiren with valsartan oral solution in patients with diabetes [see Drug Interactions (7) ]. Known hypersensitivity ( 4 ) Patients with diabetes on aliskiren ( 4 )

6 ADVERSE REACTIONS Hypertension: Most common adverse reactions are headache, dizziness, 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 Lifsa Drugs LLC at 1-800-223-1467 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies 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 fatigue (2% vs. 1%) and abdominal pain (2% vs. 1%). Headache, dizziness, upper respiratory infection, cough, diarrhea, rhinitis, sinusitis, nausea, pharyngitis, edema, and arthralgia occurred at a more than 1% rate, but at about the same incidence in placebo and valsartan patients. 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 0.2% of valsartan patients) are listed below. It cannot be determined whether these events were causally related to valsartan. Body as a Whole: Allergic reaction and asthenia Cardiovascular: Palpitations Dermatologic: Pruritus and rash Digestive: Constipation, dry mouth, dyspepsia and flatulence Musculoskeletal: Backpain, muscle cramps, and myalgia Neurologic and Psychiatric: Anxiety, insomnia, paresthesia, and somnolence Respiratory: Dyspnea Special Senses: Vertigo Urogenital: Impotence Other reported events seen less frequently in clinical trials included chest pain, syncope, anorexia, vomiting, and angioedema. Pediatric Hypertension Valsartan has been evaluated for safety in over 400 pediatric patients aged 6 to 17 years and more than 160 pediatric patients aged 6 months to 5 years. No relevant differences were identified between the adverse experience profile for pediatric patients aged 6 to 16 years and that previously reported for adult patients. Headache and hyperkalemia were the most common adverse events suspected to be study drug-related in older children (6 to 17 years old) and younger children (6 months to 5 years old), respectively. Hyperkalemia was mainly observed in children with underlying renal disease. Neurocognitive and developmental assessment of pediatric patients aged 6 to 16 years revealed no overall clinically relevant adverse impact after treatment with valsartan for up to 1 year. Valsartan is not recommended for ped …

7 DRUG INTERACTIONS 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 ) NSAIDs increase risk of renal impairment and loss of antihypertensive effect ( 7 ) Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia ( 7 ) Lithium: Increases in serum lithium concentrations and lithium toxicity ( 7 ) 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, monitor serum potassium. 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. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on valsartan oral solution and other agents that affect the RAS. Do not coadminister aliskiren with valsartan oral solution in patients with diabetes. Avoid use of aliskiren with valsartan oral solution 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, including valsartan. Monitor serum lithium levels during concomitant use.

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended. ( 8.2 ). Pediatrics: Efficacy and safety data support use in 6-16 year old patients; use is not recommended in patients <6 years old ( 6.1 , 8.4 ) 8.1 Pregnancy Risk Summary Valsartan oral solution 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 ) . Studies in rats and rabbits with valsartan showed fetotoxicity only at maternally toxic doses (see Data ) . When pregnancy is detected, discontinue valsartan oral solution 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 malformations and miscarriage in clinically recognized pregnancies is 2-4%, and 15-20%, 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 and 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 valsartan oral solution 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. Closely observe infants with histories of in utero exposure to valsartan oral solution for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occur in neonates with a history of in utero exposure to valsartan oral solution, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function. Data Animal Data No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day …

12.1 Mechanism of Action 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. 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 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.

11 DESCRIPTION Valsartan is a nonpeptide, orally active, and specific angiotensin II receptor blocker acting on the AT 1 receptor subtype. Valsartan is chemically described as N -(1-oxopentyl)- N -[[2′-(1 H -tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl]-L-valine. Its empirical formula is C 24 H 29 N 5 O 3 , its molecular weight is 435.5, and its structural formula is: Valsartan is an off white to white powder. It is soluble in methanol, freely soluble in anhydrous ethanol, sparingly soluble in methylene chloride, practically insoluble in water. Valsartan oral solution is formulated at a concentration of 4 mg/mL valsartan, as a clear, colorless solution with grape flavor, free from any visible foreign and particulate matter, free of precipitation and hazy mass. The inactive ingredients are: grape flavor, methylparaben, poloxamer, potassium sorbate, propylene glycol, sodium hydroxide, purified water, trisodium citrate dihydrate, and sucralose. Each 5 mL of Valsartan oral solution contains 18.46 mg of sodium. Valsartan Oral Solution Structure

10 OVERDOSAGE Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Depressed level of consciousness, circulatory collapse and shock have been reported. If symptomatic hypotension should occur, supportive treatment should be instituted. Valsartan is not removed from the plasma by hemodialysis. Valsartan was without grossly observable adverse effects at single oral doses up to 2000 mg/kg in rats and up to 1000 mg/kg in marmosets, except for salivation and diarrhea in the rat and vomiting in the marmoset at the highest dose (60 and 31 times, respectively, the maximum recommended human dose on a mg/m 2 basis). (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)

16 HOW SUPPLIED/STORAGE AND HANDLING Valsartan Oral Solution containing 4 mg/mL valsartan, USP for oral administration. Each mL contains 4 mg valsartan. It is a clear, colorless solution and is supplied as: White HDPE bottles of 120 mL: NDC 72888-184-48 White HDPE bottles of 473 mL: NDC 72888-184-13 Store at 20 °C-25 °C (68 °F-77 °F); excursions permitted to 15 °C -30 °C (59 °F -86 °F) [see USP Controlled Room Temperature]. Dispense in tight container (USP).