Amlodipine And Valsartan

1 INDICATIONS AND USAGE Amlodipine and valsartan is the combination tablet of amlodipine, a dihydropyridine calcium channel blocker (DHP CCB), and valsartan, an angiotensin II receptor blocker (ARB). Amlodipine and valsartan is indicated for the treatment of hypertension, to lower blood pressure: In patients not adequately controlled on monotherapy (1) As initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals (1) Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. 1.1 Hypertension Amlodipine and valsartan is 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 and the angiotensin II receptor blocker (ARB) class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with amlodipine and 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 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 (for example, 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. Amlodipine and valsartan is indicated for the treatment of hypertension. Amlodipine and valsartan may be used in patients whose blood pressure is not adequately controlled on either monotherapy. Amlodipine and valsartan may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals. The choice of amlodipine and valsartan as initial therapy for hypertension should be based on an assessment of potential benefits and risks including whether the patient is likely to tolerate the lowest dose of amlodipine and valsartan. Patients with stage 2 hypertension (moderate or severe) are at a relatively higher 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 study [see Clinical Studies (14)] provide estimates of the probability of reaching a blood pressure goal with amlodipine and valsartan compared to amlodipine or valsartan monotherapy. The figures below provide estimates of the likelihood of achieving systolic or diastolic blood pressure control with amlodipine and valsartan 10/320 mg, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was estimated by logistic regression modeling. The estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures. Figure 1: Probability of Achieving Systolic Blood Pressure <140 mmHg at Week 8 Figure 2: Probability of Achieving Diastolic Blood Pressure <90 mmHg at Week 8 Figure 3: Probability of Achieving Systolic Blood Pressure <130 mmHg at Week 8 Figure 4: Probability of Achieving Diastolic Blood Pressure <80 mmHg at Week 8 For example, a patient with a baseline blood pressure of 160/100 mmHg has about a 67% likelihood of achieving a goal of < 140 mmHg (systolic) and 80% likelihood of achieving < 90 mmHg (diastolic) on amlodipine alone, and the likelihood of achieving these goals on valsartan alone is about 47% (systolic) or 62% (diastolic). The likelihood of achieving these goals on amlodipine and valsartan rises to about 80% (systolic) or 85% (diastolic). The likelihood of achieving these goals on placebo is about 28% (systolic) or 37% (diastolic). Figure 1: Probability of Achieving Systolic Blood Pressure <140 mmHg at Week 8 Figure 2: Probability of Achieving Diastolic Blood Pressure <90 mmHg at Week 8 Figure 3: Probability of Achieving Systolic Blood Pressure <130 mmHg at Week 8 Figure 4: Probability of Achieving Diastolic Blood Pressure <80 mmHg at Week 8

2 DOSAGE AND ADMINISTRATION General Considerations: Majority of effect attained within 2 weeks (2.1) May be administered with other antihypertensive agents (2.1) Hypertension: May be used as add-on therapy for patients not controlled on monotherapy (2.2) Patients who experience dose-limiting adverse reactions on monotherapy may be switched to amlodipine and valsartan containing a lower dose of that component (2.2) May be substituted for titrated components (2.3) When used as initial therapy: Initiate with 5/160 mg, then titrate upwards as necessary to a maximum of 10/320 mg once daily (2.4) 2.1 General Considerations Dose once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of one 10/320 mg tablet once daily as needed to control blood pressure. The majority of the antihypertensive effect is attained within 2 weeks after initiation of therapy or a change in dose. Amlodipine and valsartan may be administered with other antihypertensive agents. 2.2 Add-on Therapy A patient whose blood pressure is not adequately controlled with amlodipine (or another dihydropyridine calcium-channel blocker) alone or with valsartan (or another ARB) alone may be switched to combination therapy with amlodipine and valsartan. A patient who experiences dose-limiting adverse reactions on either component alone may be switched to amlodipine and valsartan containing a lower dose of that component in combination with the other to achieve similar blood pressure reductions. The clinical response to amlodipine and valsartan 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 10/320 mg. 2.3 Replacement Therapy For convenience, patients receiving amlodipine and valsartan from separate tablets may instead wish to receive tablets of amlodipine and valsartan containing the same component doses. 2.4 Initial Therapy A patient may be initiated on amlodipine and valsartan if it is unlikely that control of blood pressure would be achieved with a single agent. The usual starting dose is amlodipine and valsartan 5/160 mg once daily in patients who are not volume-depleted.

6 ADVERSE REACTIONS In placebo-controlled clinical trials, discontinuation due to side effects occurred in 1.8% of patients in the amlodipine and valsartan-treated patients and 2.1% in the placebo-treated group. The most common reasons for discontinuation of therapy with amlodipine and valsartan were peripheral edema and vertigo. The adverse experiences that occurred in clinical trials (≥ 2% of patients) at a higher incidence than placebo included peripheral edema, nasopharyngitis, upper respiratory tract infection, and dizziness. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Strides Pharma Inc. at 1-877-244-9825 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials 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. Studies with Amlodipine and Valsartan: Amlodipine and valsartan has been evaluated for safety in over 2600 patients with hypertension; over 1440 of these patients were treated for at least 6 months and over 540 of these patients were treated for at least 1 year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The hazards [see Warnings and Precautions (5)] of valsartan are generally independent of dose; those of amlodipine are a mixture of dose-dependent phenomena (primarily peripheral edema) and dose-independent phenomena, the former much more common than the latter. The overall frequency of adverse reactions was neither dose-related nor related to gender, age, or race. In placebo-controlled clinical trials, discontinuation due to side effects occurred in 1.8% of patients in the amlodipine and valsartan‑treated patients and 2.1% in the placebo-treated group. The most common reasons for discontinuation of therapy with amlodipine and valsartan were peripheral edema (0.4%), and vertigo (0.2%). The adverse reactions that occurred in placebo-controlled clinical trials in at least 2% of patients treated with amlodipine and valsartan but at a higher incidence in amlodipine/valsartan patients (n=1437) than placebo (n=337) included peripheral edema (5.4% vs 3.0%), nasopharyngitis (4.3% vs 1.8%), upper respiratory tract infection (2.9% vs 2.1%) and dizziness (2.1% vs 0.9%). Orthostatic events (orthostatic hypotension and postural dizziness) were seen in less than 1% of patients. Studies with Valsartan: Diovan ® has been evaluated for safety in more than 4000 hypertensive patients in clinical trials. In trials in which valsartan was compared to an angiotensin-converting enzyme (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<0.001). Clinical Lab Test Findings: 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 5.5% of amlodipine and valsartan-treated patients compared to 4.7% of placebo-treated patients. In heart failure patients, greater than 50% increases in BUN were observed in 16.6% of valsartan-treated patients compared to 6.3% of placebo-treated patients [see Warnings and Precautions (5.4)]. Neutropenia: Neutropenia was observed in 1.9% of patients treated with Diovan 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 : 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: 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 reports of hepatitis Musculoskeletal: Rhabdomyolysis Renal: Impaired renal function, renal failure Dermatologic: Alopecia, bullous dermatitis Blood and Lymphatic: Thrombocytopenia Vascular: Vasculitis

12.3 Pharmacokinetics Amlodipine Peak plasma concentrations of amlodipine are reached 6 to 12 hours after administration of amlodipine alone. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food. The apparent volume of distribution of amlodipine is 21 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients. Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Elimination of amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing. Valsartan Following oral administration of valsartan alone peak plasma concentrations of valsartan are reached in 2 to 4 hours. Absolute bioavailability is about 25% (range 10% to 35%). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (C max ) by about 50%. The steady state volume of distribution of valsartan after intravenous administration is 17 L, indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin. Valsartan shows biexponential decay kinetics following intravenous administration with an average elimination half-life of about 6 hours. The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance). Amlodipine and Valsartan Following oral administration of amlodipine and valsartan in normal healthy adults, peak plasma concentrations of valsartan and amlodipine are reached in 3 and 6 to 8 hours, respectively. The rate and extent of absorption of valsartan and amlodipine from amlodipine and valsartan are the same as when administered as individual tablets. The bioavailabilities of amlodipine and valsartan are not altered by the coadministration of food. Amlodipine and Valsartan may be administered with or without food. Specific Populations Geriatric Amlodipine: Elderly patients have decreased clearance of amlodipine with a resulting increase in peak plasma levels, elimination half-life and AUC. Valsartan: Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary. Gender Valsartan: Pharmacokinetics of valsartan does not differ significantly between males and females. Renal Insufficiency Amlodipine: The pharmacokinetics of amlodipine is not significantly influenced by renal impairment. Valsartan: There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, exercise care with dosing of valsartan. Hepatic Insufficiency Amlodipine: Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase in AUC of approximately 40% to 60%. Valsartan: On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with liver disease. Drug Interactions Amlodipine In vitro data in human plasma indicate that amlodipine has no effect on the protein binding of digoxin, phenytoin, warfarin and indomethacin. Impact of Other Drugs on Amlodipine Coadministered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine. CYP3A Inhibitors : Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent [see Drug Interactions (7)]. Impact of Amlodipine on Other Drugs Coadministered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time. Simvastatin : Coadministration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone [see Drug Interactions (7)]. Cyclosporine : A prospective study in renal transplant patients (N=11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with amlodipine [see Drug Interactions (7)]. Tacrolimus : A prospective study in healthy Chinese volunteers (N=9) with CYP3A5 expressers showed a 2.5-to 4-fold increase in tacrolimus exposure when concomitantly administered with amlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressers (N=6). However, a 3-fold increase in plasma exposure to tacrolimus in a renal transplant patient (CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported. Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excluded with these drugs [see Drug Interactions (7)]. Valsartan No clinically significant pharmacokinetic interactions were observed when valsartan was coadministered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone. Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin. Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Coadministration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.