Amlodipine, Valsartan and Hydrochlorothiazide

Amlodipine, 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 amlodipine, hydrochlorothiazide, and the ARB class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with amlodipine, 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 1 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. Limitation of Use Amlodipine, valsartan and hydrochlorothiazide tablets are not indicated for the initial therapy of hypertension [see Dosage and Administration (2) ] . Amlodipine, valsartan and hydrochlorothiazide tablets are a combination of amlodipine, a dihydropyridine calcium channel blocker (DHP CCB), valsartan, an angiotensin II receptor blocker (ARB), and hydrochlorothiazide, a thiazide diuretic. Amlodipine, 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. ( 1 ) Limitation of Use Amlodipine, valsartan and hydrochlorothiazide tablets are not indicated for initial treatment of hypertension.

Amlodipine, Valsartan and Hydrochlorothiazide Tablets USP, 5 mg/160 mg/12.5 mg – White colored, ovaloid, beveled edge, biconvex film-coated tablet, debossed with ‘J’ on one side and ‘88’ on the other side. Amlodipine, Valsartan and Hydrochlorothiazide Tablets USP, 10 mg/160 mg/12.5 mg – Pale yellow colored, ovaloid, beveled edge, biconvex film-coated tablet, debossed with ‘J’ on one side and ‘90’ on the other side. Amlodipine, Valsartan and Hydrochlorothiazide Tablets USP, 5 mg/160 mg/25 mg – Yellow colored, ovaloid, beveled edge, biconvex film-coated tablet, debossed with ‘J’ on one side and ‘89’ on the other side. Amlodipine, Valsartan and Hydrochlorothiazide Tablets USP, 10 mg/160 mg/25 mg – Brown colored, ovaloid, beveled edge, biconvex film-coated tablet, debossed with ‘J’ on one side and ‘91’ on the other side. Amlodipine, Valsartan and Hydrochlorothiazide Tablets USP, 10 mg/320 mg/25 mg – Brown colored, ovaloid, beveled edge, film-coated tablet, debossed with ‘J’ on one side and ‘92’ on the other side. Tablets: (amlodipine/valsartan/hydrochlorothiazide) 5 mg/160 mg/12.5 mg, 10 mg/160 mg/12.5 mg, 5 mg/160 mg/25 mg, 10 mg/160 mg/25 mg and 10 mg/320 mg/25 mg ( 3 )

Do not use in patients with anuria, hypersensitivity to other sulfonamide-derived drugs, or hypersensitivity to any component of this product. Do not coadminister aliskiren with amlodipine, valsartan and hydrochlorothiazide tablets in patients with diabetes [see Drug Interactions (7) ]. Anuria ( 4 ) Hypersensitivity to sulfonamide-derived drugs ( 4 ) Known hypersensitivity to any component ( 4 ) Do not coadminister aliskiren with amlodipine, valsartan and hydrochlorothiazide tablets in patients with diabetes ( 4 )

Hypotension: Correct volume depletion prior to initiation ( 5.2 ) Increased angina and/or myocardial infarction ( 5.3 ) Monitor renal function and potassium in susceptible patients ( 5.4 , 5.5 ) Exacerbation or activation of systemic lupus erythematosus ( 5.7 ) Observe for signs of fluid or electrolyte imbalance ( 5.9 ) Acute angle-closure glaucoma ( 5.10 )

5.1 Fetal Toxicity Valsartan Amlodipine, 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. When pregnancy is detected, discontinue amlodipine, valsartan and hydrochlorothiazide as soon as possible [see Use in Specific Populations (8.1) ] . Hydrochlorothiazide 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.

5.2 Hypotension in Volume- or Salt-Depleted Patients Excessive hypotension, including orthostatic hypotension, was seen in 1.7% of patients treated with the maximum dose of amlodipine, valsartan and hydrochlorothiazide (10 mg/320 mg/25 mg) compared to 1.8% of valsartan/hydrochlorothiazide (320 mg/25 mg) patients, 0.4% of amlodipine/valsartan (10 mg/320 mg) patients, and 0.2% of hydrochlorothiazide/amlodipine (25 mg/10 mg) patients in a controlled trial in patients with moderate to severe uncomplicated hypertension. In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers. Correct this condition prior to administration of amlodipine, valsartan and hydrochlorothiazide. Amlodipine, valsartan and hydrochlorothiazide have not been studied in patients with heart failure, recent myocardial infarction, or in patients undergoing surgery or dialysis. Patients with heart failure or post-myocardial infarction patients given valsartan 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. Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Do not initiate treatment with amlodipine, valsartan and hydrochlorothiazide in patients with aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy. If excessive hypotension occurs with amlodipine, valsartan and hydrochlorothiazide, place the patient in a 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 Increased Angina and/or Myocardial Infarction Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.

5.4 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 amlodipine, 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 amlodipine, valsartan and hydrochlorothiazide [see Drug Interactions (7) ] .

5.5 Potassium Abnormalities In the controlled trial of amlodipine, valsartan and hydrochlorothiazide in moderate to severe hypertensive patients, the incidence of hypokalemia (serum potassium < 3.5 mEq/L) at any time post-baseline with the maximum dose of amlodipine, valsartan and hydrochlorothiazide (10 mg/320 mg/25 mg) was 10% compared to 25% with hydrochlorothiazide/amlodipine (25 mg/10 mg), 7% with valsartan/hydrochlorothiazide (320 mg/25 mg), and 3% with amlodipine/valsartan (10 mg/320 mg). One patient (0.2%) discontinued therapy due to an adverse event of hypokalemia in each of the amlodipine, valsartan and hydrochlorothiazide and hydrochlorothiazide/amlodipine groups. The incidence of hyperkalemia (serum potassium > 5.7 mEq/L) was 0.4% with amlodipine, valsartan and hydrochlorothiazide compared to 0.2% to 0.7% with the dual therapies. Some patients with heart failure have developed increases in potassium on valsartan. 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 the diuretic and/or valsartan may be required. 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 (e.g., muscular weakness, paresis, or ECG alterations), amlodipine, valsartan and hydrochlorothiazide should be discontinued. Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides.

5.6 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.

5.7 Systemic Lupus Erythematosus Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

5.8 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 amlodipine, valsartan and hydrochlorothiazide and lithium [see Drug Interactions (7) ].

5.9 Metabolic Imbalances Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving amlodipine, valsartan and hydrochlorothiazide.

5.10 Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. […]

Most common adverse events (≥ 2% incidence) are dizziness, peripheral edema, headache, dyspepsia, fatigue, muscle spasms, back pain, nausea, and nasopharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 clinical practice. In the controlled trial of amlodipine, valsartan and hydrochlorothiazide, where only the maximum dose (10 mg/320 mg/25 mg) was evaluated, safety data were obtained in 582 patients with hypertension. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall frequency of adverse reactions was similar between men and women, younger (< 65 years) and older (≥ 65 years) patients, and black and white patients. In the active controlled clinical trial, discontinuation because of adverse events occurred in 4% of patients treated with amlodipine, valsartan and hydrochlorothiazide 10 mg/320 mg/25 mg compared to 2.9% of patients treated with valsartan/hydrochlorothiazide 320 mg/25 mg, 1.6% of patients treated with amlodipine/valsartan 10 mg/320 mg, and 3.4% of patients treated with hydrochlorothiazide/amlodipine 25 mg/10 mg. The most common reasons for discontinuation of therapy with amlodipine, valsartan and hydrochlorothiazide were dizziness (1%) and hypotension (0.7%). The most frequent adverse events that occurred in the active controlled clinical trial in at least 2% of patients treated with amlodipine, valsartan and hydrochlorothiazide are presented in the following table. Preferred Term Amlodipine/ Valsartan/ Hydrochlorothiazide 10 mg/320 mg/25 mg N=582 n (%) Valsartan/ Hydrochlorothiazide 320 mg/25 mg N=559 n (%) Amlodipine/ Valsartan 10 mg/320 mg N=566 n (%) Hydrochlorothiazide/ Amlodipine 25 mg/10 mg N=561 n (%) Dizziness 48 (8.2) 40 (7.2) 14 (2.5) 23 (4.1) Edema 38 (6.5) 8 (1.4) 65 (11.5) 63 (11.2) Headache 30 (5.2) 31 (5.5) 30 (5.3) 40 (7.1) Dyspepsia 13 (2.2) 5 (0.9) 6 (1.1) 2 (0.4) Fatigue 13 (2.2) 15 (2.7) 12 (2.1) 8 (1.4) Muscle spasms 13 (2.2) 7 (1.3) 7 (1.2) 5 (0.9) Back pain 12 (2.1) 13 (2.3) 5 (0.9) 12 (2.1) Nausea 12 (2.1) 7 (1.3) 10 (1.8) 12 (2.1) Nasopharyngitis 12 (2.1) 13 (2.3) 13 (2.3) 12 (2.1) Orthostatic events (orthostatic hypotension and postural dizziness) were seen in 0.5% of patients. Valsartan Valsartan has been evaluated for safety in more than 4000 hypertensive patients in clinical trials. 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, hydrochlorothiazide, or lisinopril were 20%, 19%, and 69%, respectively (p < 0.001). Clinical Laboratory Test Findings Clinical laboratory test findings for amlodipine, valsartan and hydrochlorothiazide were obtained in a controlled trial of amlodipine, valsartan and hydrochlorothiazide administered at the maximal dose of 10 mg/320 mg/25 mg compared to maximal doses of dual therapies, i.e., valsartan/hydrochlorothiazide 320 mg/25 mg, amlodipine/valsartan 10 mg/320 mg, and hydrochlorothiazide/amlodipine 25 mg/10 mg. Findings for the components of amlodipine, valsartan and hydrochlorothiazide were obtained from other trials. Creatinine: In heart failure patients, greater than 50% increases in creatinine were observed in 3.9% of valsartan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients. Blood Urea Nitrogen (BUN): In hypertensive patients, greater than 50% increases in BUN were observed in 30% of amlodipine, valsartan and hydrochlorothiazide-treated patients compared to 29% of valsartan/hydrochlorothiazide patients, 15.8% of amlodipine/valsartan patients, and 18.5% of hydrochlorothiazide/amlodipine patients. In heart failure patients, greater than 50% increases in BUN were observed in 17% of valsartan-treated patients compared to 6% of placebo-treated patients [see Warnings and Precautions (5.4) ]. Neutropenia : Neutropenia (< 1500/L) was observed in 1.9% of patients treated with valsartan and 0.8% of patients treated with placebo.

6.2 Postmarketing Experience The following additional adverse reactions have been reported in postmarketing experience. 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. Amlodipine With amlodipine, gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine. Valsartan The following additional adverse reactions have been reported in postmarketing experience with valsartan or valsartan/hydrochlorothiazide: Blood and Lymphatic: Decrease in hemoglobin, decrease in hematocrit, neutropenia Hypersensitivity : Angioedema has been reported. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Amlodipine, valsartan and hydrochlorothiazide should not be re-administered to patients who have had angioedema. Digestive : Elevated liver enzymes and reports of hepatitis Musculoskeletal: Rhabdomyolysis Renal: Impaired renal function, renal failure Dermatologic: Alopecia, bullous dermatitis Vascular: Vasculitis Nervous System: Syncope Hydrochlorothiazide The following additional adverse reactions have been reported in postmarketing experience with hydrochlorothiazide: Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma, bone marrow failure, worsening of diabetes control, hypokalemia, blood lipids increased, hyponatremia, hypomagnesemia, hypercalcemia, hypochloremic alkalosis, impotence, visual impairment. Pathological changes in the parathyroid gland of patients with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcemia occurs, further diagnostic evaluation is necessary. Non-melanoma Skin Cancer: Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥ 50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

No drug interaction studies have been conducted with amlodipine, valsartan and hydrochlorothiazide and other drugs, although studies have been conducted with the individual components. A pharmacokinetic drug-drug interaction study has been conducted to address the potential for pharmacokinetic interaction between the triple combination, amlodipine, valsartan and hydrochlorothiazide, and the corresponding 3 double combinations. No clinically relevant interaction was observed. Amlodipine Impact of Other Drugs on Amlodipine CYP3A Inhibitors Coadministration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is coadministered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology (12.3) ] . CYP3A Inducers No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is coadministered with CYP3A inducers (e.g., rifampicin, St. John’s Wort). Sildenafil Monitor for hypotension when sildenafil is coadministered with amlodipine [see Clinical Pharmacology (12.2) ] . Impact of Amlodipine on Other Drugs Simvastatin Coadministration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily [see Clinical Pharmacology (12.3) ] . Immunosuppressants Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when coadministered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology (12.3) ] . 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, 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. 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 coadminister aliskiren with valsartan in patients with diabetes. Avoid use of aliskiren with valsartan in patients with renal impairment (GFR < 60 mL/min). Valsartan – 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 amlodipine, valsartan and hydrochlorothiazide. 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. Non-Steroidal Anti-inflammatory Drugs (NSAIDs and COX-2 selective inhibitors): When amlodipine, valsartan and hydrochlorothiazide and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of 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. If simvastatin is coadministered with amlodipine, do not exceed doses greater than 20 mg daily of simvastatin. ( 7 ) 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 Drug (NSAID) use may lead to increased risk of renal impairment and loss of anti-hypertensive effect. ( 7 ) Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia. ( 7 )

Lactation: Breastfeeding is not recommended ( 8.2 ) Geriatric Patients: Not recommended for initial therapy ( 8.5 ) Hepatic Impairment: Not recommended for initial therapy ( 8.7 )

8.1 Pregnancy Risk Summary Amlodipine, 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 amlodipine, 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 Amlodipine, valsartan and hydrochlorothiazide for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to Amlodipine, 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 (preeclampsia), 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 and Amlodipine In rats, administered 20 mg/kg/day amlodipine plus 320 mg/kg/day valsartan, treatment-related maternal and fetal effects (developmental delays and alterations noted in the presence of significant maternal toxicity) were noted with the high dose combination. This corresponds to dose multiples of 9 and 19.5 times, respectively, the maximum recommended human dose (MRHD) of 10 mg/day for amlodipine and 320 mg/day for valsartan (based on body surface area and considering a 60 kg patient). Hydrochlorothiazide No teratogenic effects were observed when hydrochlorothiazide was administered to mice and rats via gavage at doses of up to 3,000 and 1,000 mg/kg/day (608 and 405 times the MRHD), on gestation days 6 through 15.

8.2 Lactation Risk Summary There is limited information regarding the presence of amlodipine, valsartan and hydrochlorothiazide in human milk, the effects on the breastfed infant, or the effects on milk production. Hydrochlorothiazide is present in human milk and valsartan is present in rat milk. Limited published studies report that amlodipine is present in human milk. Because of the potential for serious adverse reactions in breastfed infants, advise a nursing woman that breastfeeding is not recommended during treatment with amlodipine, valsartan and hydrochlorothiazide. 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 safety and effectiveness of amlodipine, valsartan and hydrochlorothiazide in pediatric patients have not been established.

8.5 Geriatric Use Amlodipine Clinical studies of amlodipine besylate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40% to 60% [see Clinical Pharmacology (12.3) ] . The recommended starting dose of amlodipine 2.5 mg is not an available strength with amlodipine, valsartan and hydrochlorothiazide [see Clinical Studies (14) ] .

8.6 Renal Impairment Safety and effectiveness of amlodipine, valsartan and hydrochlorothiazide in patients with severe renal impairment (CrCl < 30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCl 60 to 90 mL/min) or moderate (CrCl 30 to 60 mL/min) renal impairment.

8.7 Hepatic Impairment Amlodipine Exposure to amlodipine is increased in patients with hepatic insufficiency. The recommended initial dose of amlodipine in patients with hepatic impairment is 2.5 mg, which is not an available strength with amlodipine, valsartan and hydrochlorothiazide [see Clinical Pharmacology (12.3) ] . Valsartan No dose adjustment is necessary for patients with mild-to-moderate disease. No dosing recommendations can be provided for patients with severe liver disease. Hydrochlorothiazide Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

The active ingredients of amlodipine, valsartan and hydrochlorothiazide target 3 separate mechanisms involved in blood pressure regulation. Specifically, amlodipine blocks the contractile effects of calcium on cardiac and vascular smooth muscle cells; valsartan blocks the vasoconstriction and sodium retaining effects of angiotensin II on cardiac, vascular smooth muscle, adrenal and renal cells; and hydrochlorothiazide directly promotes the excretion of sodium and chloride in the kidney leading to reductions in intravascular volume. A more detailed description of the mechanism of action of each individual component follows. Amlodipine Amlodipine is a dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. Valsartan 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 20000-fold) for the AT 1 receptor than for the AT 2 receptor. The increased plasma levels of angiotensin 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. Hydrochlorothiazide Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is unknown.