Valsartan and Hydrochlorothiazide

1 INDICATIONS AND USAGE Valsartan and hydrochlorothiazide tablets are 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 hydrochlorothiazide and the angiotensin II receptor blocker (ARB) class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with valsartan and hydrochlorothiazide 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 have also 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. Add-On Therapy Valsartan and hydrochlorothiazide tablets may be used in patients whose blood pressure is not adequately controlled on monotherapy. Replacement Therapy Valsartan and hydrochlorothiazide tablets may be substituted for the titrated components. Initial Therapy Valsartan and hydrochlorothiazide tablets may be used as initial therapy in patients who are likely to need multiple drugs to achieve blood pressure goals. The choice of valsartan and hydrochlorothiazide tablets as initial therapy for hypertension should be based on an assessment of potential benefits and risks. Patients with stage 2 hypertension are at a relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared to monotherapy. Individual blood pressure goals may vary based upon the patient’s risk. Data from the high dose multifactorial trial [see Clinical Studies (14.1) ] provides estimates of the probability of reaching a target blood pressure with valsartan an…

2 DOSAGE AND ADMINISTRATION Dose once daily. Titrate as needed to a maximum dose of 320 mg/25 mg. (2) May be used as add-on/switch therapy for patients not adequately controlled on any of the components (valsartan or HCTZ). (2) May be substituted for titrated components. (2.3) 2.1 General Considerations The usual starting dose is valsartan and hydrochlorothiazide tablets 160 mg/12.5 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of one 320 mg/25 mg tablet once daily as needed to control blood pressure [see Clinical Studies (14.2) ]. Maximum antihypertensive effects are attained within 2 to 4 weeks after a change in dose. 2.2 Add-On Therapy A patient whose blood pressure is not adequately controlled with valsartan (or another ARB) alone or hydrochlorothiazide alone may be switched to combination therapy with valsartan and hydrochlorothiazide tablets. A patient who experiences dose-limiting adverse reactions on either component alone may be switched to valsartan and hydrochlorothiazide tablets containing a lower dose of that component in combination with the other to achieve similar blood pressure reductions. The clinical response to valsartan and hydrochlorothiazide tablets should be subsequently evaluated and if blood pressure remains uncontrolled after 3 to 4 weeks of therapy, the dose may be titrated up to a maximum of 320 mg/25 mg. 2.3 Replacement Therapy Valsartan and hydrochlorothiazide tablets may be substituted for the titrated components. 2.4 Initial Therapy Valsartan and hydrochlorothiazide tablets are not recommended as initial therapy in patients with intravascular volume depletion [see Warnings and Precautions (5.2) ]. 2.5 Use with Other Antihypertensive Drugs Valsartan and hydrochlorothiazide tablets may be administered with other antihypertensive agents.

5 WARNINGS AND PRECAUTIONS Hypotension: Correct volume depletion prior to initiation. (5.2) Observe for signs of fluid or electrolyte imbalance. (5.9) Monitor renal function and potassium in susceptible patients. (5.3, 5.7) Exacerbation or activation of systemic lupus erythematosus. (5.5) Acute angle-closure glaucoma. (5.8) 5.1 Fetal Toxicity Valsartan and hydrochlorothiazide 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. Thiazides cross the placenta, and use of thiazides during pregnancy is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. When pregnancy is detected, discontinue valsartan and hydrochlorothiazide as soon as possible [see Use in Specific Populations (8.1) ]. 5.2 Hypotension in Volume- and/or Salt-Depleted Patients Excessive reduction of blood pressure was rarely seen (0.7%) in patients with uncomplicated hypertension treated with valsartan and hydrochlorothiazide in controlled trials. 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 valsartan and hydrochlorothiazide, or the treatment should start under close medical supervision. If 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 valsartan and hydrochlorothiazide. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan and hydrochlorothiazide [see Drug Interactions (7) ] . 5.4 Hypersensitivity Reaction Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. 5.5 Systemic Lupus Erythematosus Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. 5.6 Lithium Interaction Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of valsartan or thiazide diuretics. Monitor lithium levels in patients receiving valsartan and hydrochlorothiazide tablets and lithium [see Drug Interactions (7) ]. 5.7 Potassium Abnormalities In the controlled trials of various doses of valsartan and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium < 3.5 mEq/L) was 3.0%; the incidence of hyperkalemia (serum potassium > 5.7 mEq/L) was 0.4%. Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically. If hypokalemia is accompanied by clinical signs …

4 CONTRAINDICATIONS Valsartan and hydrochlorothiazide tablets are contraindicated in patients who are hypersensitive to any component of this product. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Do not co-administer aliskiren with valsartan and hydrochlorothiazide tablets in patients with diabetes [see Drug Interactions (7) ] . Anuria; Hypersensitivity to any sulfonamide-derived drugs or any component; Do not co-administer aliskiren with valsartan and hydrochlorothiazide tablets in patients with diabetes. (4)

7 DRUG INTERACTIONS Valsartan and Hydrochlorothiazide: Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists or thiazides. Monitor lithium levels in patients taking valsartan and hydrochlorothiazide. Valsartan: 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. 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, co-administration 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. 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 and other agents that affect the RAS. Do not co-administer aliskiren with valsartan in patients with diabetes. Avoid use of aliskiren with valsartan in patients with renal impairment (GFR < 60 mL/min). Hydrochlorothiazide: When administered concurrently, the following drugs may interact with thiazide diuretics: Antidiabetic Drugs (oral agents and insulin) - Dosage adjustment of the antidiabetic drug may be required. Nonsteroidal Anti-inflammatory Drugs (NSAIDs and COX-2 selective inhibitors) - When valsartan and hydrochlorothiazide and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Carbamazepine - May lead to symptomatic hyponatremia. Ion exchange resins: Staggering the dosage of hydrochlorothiazide and ion exchange resins (e.g., cholestyramine, colestipol) such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of resins would potentially minimize the interaction [see Clinical Pharmacology (12.3) ]. Cyclosporine: Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-type complications. Antidiabetic drugs: Dosage adjustment of antidiabetic may be required. (7) Cholestyramine and colestipol: Reduced absorption of thiazides. (12.3) Lithium: Increased risk of lithium toxicity. Monitor serum lithium concentrations during concurrent use. (7) Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): May increase risk of renal impairment. Can reduce diuretic, natriuretic and antihypertensive effects of diuretics. (7) Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia. (7)

8.1 Pregnancy Risk Summary Valsartan and hydrochlorothiazide 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 discontinue valsartan and hydrochlorothiazide 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 Valsartan 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. 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 valsartan and hydrochlorothiazide for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to valsartan and hydrochlorothiazide, 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. Hydrochlorothiazide Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (pre-eclampsia), these drugs should not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications (e.g., heart disease) in pregnancy should be avoided. Data Animal Data Valsartan plus Hydrochlorothiazide There was no evidence of teratogenicity in mice, rats, or rabbits treated orally with valsartan at doses of up to 600, 100, and 10 mg/kg/day [9, 3.5 and 0.5 times the maximum recommended human dose (MRHD)], respectively, in combination with hydrochlorothiazide at doses up to 188, 31, and 3 mg/kg/day (38, 13 and 2 times the MRHD). Fetotoxicity was observed in association with maternal toxicity in rats at valsartan/hydrochlorothiazide…

6 ADVERSE REACTIONS The most common reasons for discontinuation of therapy with valsartan and hydrochlorothiazide were headache and dizziness. The only adverse experience that occurred in ≥ 2% of patients treated with valsartan and hydrochlorothiazide and at a higher incidence than placebo was nasopharyngitis (2.4% vs. 1.9%). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 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 reactions 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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Hypertension Valsartan and hydrochlorothiazide has been evaluated for safety in more than 5,700 patients, including over 990 treated for over 6 months, and over 370 for over 1 year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse reactions with valsartan and hydrochlorothiazide was comparable to placebo. The overall frequency of adverse reactions was neither dose-related nor related to gender, age, or race. In controlled clinical trials, discontinuation of therapy due to side effects was required in 2.3% of valsartan and hydrochlorothiazide patients and 3.1% of placebo patients. The most common reasons for discontinuation of therapy with valsartan and hydrochlorothiazide were headache and dizziness. The only adverse reaction that occurred in controlled clinical trials in at least 2% of patients treated with valsartan and hydrochlorothiazide and at a higher incidence in valsartan and hydrochlorothiazide (n=4372) than placebo (n=262) patients was nasopharyngitis (2.4% vs. 1.9%). Dose-related orthostatic effects were seen in fewer than 1% of patients. In individual trials, a dose-related increase in the incidence of dizziness was observed in patients treated with valsartan and hydrochlorothiazide. Initial Therapy-Hypertension In a clinical study in patients with severe hypertension (diastolic blood pressure ≥ 110 mmHg and systolic blood pressure ≥ 140 mmHg), the overall pattern of adverse reactions reported through six weeks of follow-up was similar in patients treated with valsartan and hydrochlorothiazide as initial therapy and in patients treated with valsartan as initial therapy. Comparing the groups treated with valsartan and hydrochlorothiazide (force-titrated to 320 mg/25 mg) and valsartan (force-titrated to 320 mg), dizziness was observed in 6% and 2% of patients, respectively. Hypotension was observed in 1% of those patients receiving valsartan and hydrochlorothiazide and 0% of patients receiving valsartan. There were no reported cases of syncope in either treatment group. Laboratory changes with valsartan and hydrochlorothiazide as initial therapy in patients with severe hypertension were similar to those reported with valsartan and hydrochlorothiazide in patients with less severe hypertension [see Clinical Studies (14.2) , Drug Interactions (7) ]. Valsartan: 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, hydrochlorothiazide, or lisinopril were 20%, 19%, 69% respectively (p < 0.001). 6.2 Postmarketing Experience The following additional adverse reactions have been reported in valsartan or valsartan/hydrochlorothiazide…