AMLODIPINE AND VALSARTAN

Amlodipine and valsartan tablets, USP are fixed combination of amlodipine and valsartan. Amlodipine and valsartan tablets, USP contains the besylate salt of amlodipine, a dihydropyridine calcium-channel blocker (CCB). Amlodipine besylate 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(4RS)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulphonate; its structural formula is Its empirical 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 AT1 receptor subtype. Valsartan is white or almost white hygroscopic powder, freely soluble in anhydrous ethanol; sparingly soluble in methylene chloride; practically insoluble in water. Valsartan’s chemical name is N-(1-oxopentyl)-N-[[2’-(1H-tetrazol-5-yl)[1,1’-biphenyl]-4-yl]methyl]-L-valine; its structural formula is Its empirical formula is C 24 H 29 N 5 O 3 and its molecular weight is 435.5. Amlodipine and valsartan tablets, USP are formulated in four strengths for oral administration with a combination of amlodipine besylate, equivalent to 5 mg or 10 mg of amlodipine free-base, 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, magnesium stearate and microcrystalline cellulose. Additionally the 5/160 mg and 5/320 mg strengths contain iron oxide red. The film coating contains hypromellose, iron oxide yellow, polyethylene glycol, talc and titanium dioxide. Amlodipine besylate Valsartan

Amlodipine and valsartan tablets, USP are the combination tablet of amlodipine, a dihydropyridine calcium channel blocker (DHP CCB), and valsartan, an angiotensin II receptor blocker (ARB). Amlodipine and valsartan tablets, USP 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, USP 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 ARB class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with amlodipine and valsartan tablets, USP. 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, USP are indicated for the treatment of hypertension. Amlodipine and valsartan tablets, USP may be used in patients whose blood pressure is not adequately controlled on either monotherapy. Amlodipine and valsartan tablets, USP 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, USP 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, USP. 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, USP 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 USP, 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 <90mmHg (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, USP 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 Figure 2 Figure 3 Figure 4

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 10/320mg 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 or without food. 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 angiotensin II receptor blocker) 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 tablets 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 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 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 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%), 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. Other adverse reactions that occurred in placebo-controlled clinical trials with amlodipine and valsartan tablets (≥0.2%) are listed below. It cannot be determined whether these events were causally related to amlodipine and valsartan tablets. Blood and Lymphatic System Disorders: Lymphadenopathy Cardiac Disorders: Palpitations, tachycardia Ear and Labyrinth Disorders: Ear pain Gastrointestinal Disorders: Diarrhea, nausea, constipation, dyspepsia, abdominal pain, abdominal pain upper, gastritis, vomiting, abdominal discomfort, abdominal distention, dry mouth, colitis General Disorders and Administration Site Conditions: Fatigue, chest pain, asthenia, pitting edema, pyrexia, edema I mmune System Disorders: Seasonal allergies Infections and Infestations: Nasopharyngitis, sinusitis, bronchitis, pharyngitis, gastroenteritis, pharyngotonsillitis, bronchitis acute, tonsillitis Injury and Poisoning: Epicondylitis, joint sprain, limb injury Metabolism and Nutrition Disorders: Gout, non-insulin-dependent diabetes mellitus, hypercholesterolemia Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, muscle spasms, pain in extremity, myalgia, osteoarthritis, joint swelling, musculoskeletal chest pain Nervous System Disorders: Headache, sciatica, paresthesia, cervicobrachial syndrome, carpal tunnel syndrome, hypoesthesia, sinus headache, somnolence Psychiatric Disorders: Insomnia, anxiety, depression Renal and Urinary Disorders: Hematuria, nephrolithiasis, pollakiuria Reproductive System and Breast Disorders: Erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders: Cough, pharyngolaryngeal pain, sinus congestion, dyspnea, epistaxis, productive cough, dysphonia, nasal congestion Skin and Subcutaneous Tissue Disorders: Pruritus, rash, hyperhidrosis, eczema, erythema Vascular Disorders: Flushing, hot flush Isolated cases of the following clinically notable adverse reactions were also observed in clinical trials: exanthema, syncope, visual disturbance, hypersensitivity, tinnitus, and hypotension. Studies with Amlodipine: Norvasc®* has been evaluated for safety in more than 11000 patients in U.S. and foreign clinical trials. Other adverse events that have been reported <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain were: Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, postural hypotension, vasculitis Central and Peripheral Nervous System: neuropathy peripheral, tremor Gastrointestinal: anorexia, dysphagia, pancreatitis, gingival hyperplasia General: allergic reaction, hot flushes, malaise, rigors, weight gain, weight loss Musculoskeletal System: arthrosis, muscle cramps Psychiatric: sexual dysfunction (male and female), nervousness, abnormal dreams, depersonalization Respiratory System: dyspnea Skin and Appendages: angioedema, erythema multiforme, rash erythematous, rash maculopapular Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus Urinary System: micturition frequency, micturition disorder, nocturia Autonomic Nervous System: sweating increased Metabolic and Nutritional: hyperglycemia, thirst Hemopoietic: leukopenia, purpura, thrombocytopenia Other events reported with amlodipine at a frequency of ≤0.1% of patients include: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia. Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina. Adverse reactions reported for amlodipine for indications other than hypertension may be found in the prescribing information for Norvasc. 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 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). Other adverse reactions, not listed above, occurring in >0.2% of patients in controlled clinical trials with valsartan are: Body as a Whole: allergic reaction, asthenia Musculoskeletal: muscle cramps Neurologic and Psychiatric: paresthesia Respiratory: sinusitis, pharyngitis Urogenital: impotence Other reported events seen less frequently in clinical trials were: angioedema. Adverse reactions reported for valsartan for indications other than hypertension may be found in the prescribing information for Diovan. Clinical Lab Test Findings: Creatinine: In hypertensive patients, greater than 50% increases in creatinine occurred in 0.4% of patients receiving amlodipine and valsartan tablets and 0.6% receiving placebo. 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. Liver Function Tests: Occasional elevations (greater than 150%) of liver chemistries occurred in amlodipine and valsartan tablets treated patients. Serum Potassium: In hypertensive patients, greater than 20% increases in serum potassium were observed in 2.8% of amlodipine and valsartan tablets-treated patients compared to 3.4% of placebo-treated patients. In heart failure patients, greater than 20% increases in serum potassium were observed in 10% of valsartan-treated patients compared to 5.1% of placebo-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. Neutropenia: Neutropenia was observed in 1.9% of patients treated with Diovan and 0.8% of patients treated with placebo. 6.2 Postmarketing Experience 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: Blood and Lymphatic: Decrease in hemoglobin, decrease in hematocrit, neutropenia, Hypersensitivity: There are rare reports of angioedema. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Amlodipine and valsartan tablets should not be re-administered to patients who have had angioedema. Digestive: Elevated liver enzymes and very rare reports of hepatitis Renal: Impaired renal function, renal failure Clinical Laboratory Tests: Hyperkalemia Dermatologic: Alopecia, bullous dermatitis Vascular: Vasculitis Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

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 Co-administration 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 co-administered 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 co-administered with CYP3A inducers. Sildenafil Monitor for hypotension when sildenafil is co-administered with amlodipine [see Clinical Pharmacology (12.2)] . Impact of Amlodipine on Other Drugs Simvastatin Co-administration 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 co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology (12.3)] . 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. Warfarin: Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin. 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. 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. CYP 450 Interactions: In vitro metabolism studies indicate that CYP 450 mediated drug interactions between valsartan and coadministered drugs are unlikely because of low extent of metabolism [see Pharmacokinetics, Valsartan (12.3)] . 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. 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 amlodipine and valsartan tablets 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, including valsartan. 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) 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 concentrations and lithium toxicity (7)