AMLODIPINE AND VALSARTAN

Amlodipine and valsartan tablets, USP are a fixed combination of amlodipine and valsartan. Amlodipine and valsartan tablets contain the besylate salt of amlodipine, a dihydropyridine calcium-channel blocker (CCB). Amlodipine besylate, USP is a white or almost white powder, slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate’s chemical name is 3-ethyl-5-methyl (4 RS )-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulfonate; its structural formula is: Its molecular formula is C 20 H 25 ClN 2 O 5 •C 6 H 6 O 3 S and its molecular weight is 567.1. Valsartan is a nonpeptide, orally active, and specific angiotensin II antagonist acting on the AT 1 receptor subtype. Valsartan, USP is a white to almost white amorphous powder, soluble in ethanol and methanol and slightly soluble in water. Valsartan’s chemical name is N -[ p -( o -1 H -tetrazol-5-ylphenyl)benzyl]- N -valeryl- L -valine; its structural formula is: Its molecular formula is C 24 H 29 N 5 O 3 and its molecular weight is 435.52. Amlodipine and valsartan tablets are formulated in 4 strengths for oral administration with a combination of amlodipine besylate (6.94 mg or 13.88 mg, equivalent to 5 mg or 10 mg of amlodipine respectively), with 160 mg, or 320 mg of valsartan providing for the following available combinations: 5/160 mg, 10/160 mg, 5/320 mg, and 10/320 mg. The inactive ingredients for all strengths of the tablets are colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, red iron oxide, sodium starch glycolate (potato), talc, titanium dioxide and yellow iron oxide. Meets USP Dissolution Test 3. Amlodipine Besylate Structural Formula Valsartan Structural Formula

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 tablets are 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 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 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 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 (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 tablets are indicated for the treatment of hypertension. Amlodipine and valsartan tablets may be used in patients whose blood pressure is not adequately controlled on either monotherapy. Amlodipine and valsartan tablets 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 tablets 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 tablets. 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 tablets 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 tablets 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. 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 tablets rises to about 80% (systolic) or 85% (diastolic). The likelihood of achieving these goals on placebo is about 28% (systolic) or 37% (diastolic). Amlodipine and Valsartan Figures 01 - 04

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 tablets 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 tablets 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 tablets. A patient who experiences dose-limiting adverse reactions on either component alone may be switched to amlodipine and valsartan tablets 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 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 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 tablets if it is unlikely that control of blood pressure would be achieved with a single agent. The usual starting dose is amlodipine and valsartan tablets 5/160 mg once daily in patients who are not volume-depleted.

Do not use in patients with known hypersensitivity to any component. Do not coadminister aliskiren with amlodipine and valsartan tablets in patients with diabetes [see Drug Interactions (7) ] . Known hypersensitivity to any component; Do not coadminister aliskiren with amlodipine and valsartan tablets in patients with diabetes ( 4 )

In placebo-controlled clinical trials, discontinuation due to side effects occurred in 1.8% of patients in the amlodipine and valsartan tablets-treated patients and 2.1% in the placebo-treated group. The most common reasons for discontinuation of therapy with amlodipine and valsartan tablets 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 Tablets Amlodipine and valsartan tablets have 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 tablets-treated patients and 2.1% in the placebo-treated group. The most common reasons for discontinuation of therapy with amlodipine and valsartan tablets 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 tablets 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 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 tablets-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

No drug interaction studies have been conducted with amlodipine and valsartan tablets and other drugs, although studies have been conducted with the individual amlodipine and valsartan components. 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 amlodipine and valsartan tablets in patients with diabetes. Avoid use of aliskiren with amlodipine and valsartan tablets in patients with renal impairment (GFR < 60 mL/min). Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use. • If simvastatin is coadministered with amlodipine, do not exceed doses greater than 20 mg daily of simvastatin ( 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 ) • Lithium: Increases in serum lithium level and lithium toxicity ( 7 ) Drug Interactions Sildenafil When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect [see Drug Interactions (7) ] . 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 Coadministration 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 coadministration 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 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.