Amlodipine

1 INDICATIONS AND USAGE NORLIQVA is a calcium channel blocker for the treatment of: Hypertension ( 1.1 ) NORLIQVA is indicated for the treatment of hypertension in adults and children 6 years of age and older, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. Coronary Artery Disease ( 1.2 ) Chronic Stable Angina Vasospastic Angina (Prinzmetal's or Variant Angina) Angiographically Documented Coronary Artery Disease in patients without heart failure or an ejection fraction <40% 1.1 Hypertension NORLIQVA® is indicated for the treatment of hypertension, to lower blood pressure in adults and children 6 years of age and older. 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 NORLIQVA. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality 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. NORLIQVA may be used alone or in combination with other antihypertensive agents. 1.2 Coronary Artery Disease (CAD) Chronic Stable Angina NORLIQVA is indicated for the symptomatic treatment of chronic stable angina. NORLIQVA may be used alone or in combination with other antianginal agents. Vasospastic Angina (Prinzmetal's or Variant Angina) NORLIQVA is indicated for the treatment of confirmed or suspected vasospastic angina. NORLIQVA may be used as monotherapy or in combination with other antianginal agents. Angiographically Documented CAD In patients with recently documented CAD by angiography and without heart failure or an ejection fraction <40%, NORLIQVA is indicated to reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure.

2 DOSAGE AND ADMINISTRATION Adult recommended starting dose: 5 mg orally once daily with a maximum of 10 mg orally once daily. ( 2.1 ) Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg orally once daily. ( 2.1 ) Pediatric starting dose: 2.5 mg to 5 mg orally once daily. ( 2.2 ) 2.1 Adults The usual initial antihypertensive oral dose of NORLIQVA is 5 mg orally once daily, and the maximum dose is 10 mg orally once daily. Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg orally once daily and this dose may be used when adding NORLIQVA to other antihypertensive therapy [see Clinical Pharmacology (12.3) ] . Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps. Titrate more rapidly, however, if clinically warranted, provided the patient is assessed frequently. Angina : The recommended dose for chronic stable or vasospastic angina is 5 mg to 10 mg orally once daily, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg orally once daily for adequate effect. Coronary artery disease : The recommended dose range for patients with coronary artery disease is 5 mg to 10 mg orally once daily. In clinical studies, the majority of patients required 10 mg [see Clinical Studies (14.4) ] . 2.2 Children The effective antihypertensive oral dose in pediatric patients ages 6 years of age and older is 2.5 mg to 5 mg orally once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients [see Clinical Pharmacology (12.4) , Clinical Studies (14.1) ] .

6 ADVERSE REACTIONS The most common adverse reactions are nausea, anorexia, and bloating. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact CMP Pharma, Inc. at 1-844-321-1443 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. Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with amlodipine was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most commonly reported adverse reactions more frequent than placebo are reflected in the table below. The incidence (%) of adverse reactions that occurred in a dose-related manner are as follows: Amlodipine Placebo 2.5 mg N=275 5 mg N=296 10 mg N=268 N=520 Edema 1.8 3.0 10.8 0.6 Dizziness 1.1 3.4 3.4 1.5 Flushing 0.7 1.4 2.6 0.0 Palpitation 0.7 1.4 4.5 0.6 Other adverse reactions that were not clearly dose-related but were reported include: Amlodipine (%) (N=1730) Placebo (%) (N=1250) Fatigue 4.5 2.8 Nausea 2.9 1.9 For several adverse reactions that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table: Amlodipine Placebo Male=% (N=1218) Female=% (N=512) Male=% (N=914) Female=% (N=336) Edema 5.6 14.6 1.4 5.1 Flushing 1.5 4.5 0.3 0.9 Palpitations 1.4 3.3 0.9 0.9 Somnolence 1.3 1.6 0.8 0.3 6.2 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. General: gynecomastia Hepatic: jaundice and hepatic enzyme elevations, some requiring hospitalization Neurologic: extrapyramidal disorder

12.3 Pharmacokinetics Absorption Amlodipine reaches peak plasma concentration (C max ) within 6.5 hours following oral administration of NORLIQVA. Absolute bioavailability of amlodipine has been estimated to be between 64 and 90%. Effect of food Administration with a high- fat, high-calorie meal did not have a significant effect on the C max and AUC of NORLIQVA. Distribution Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing. Elimination Metabolism 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 Excretion Elimination from the plasma is biphasic with a mean terminal elimination half-life of 52 hours. Specific Populations Geriatric Patients The renal clearance of amlodipine is lower in elderly patients compared to younger adults. This results in increase in AUC of approximately 40-60% [see Dosage & Administration (2.1) ] . Pediatric Patients Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults. Patients with Renal Impairment The pharmacokinetics of amlodipine is not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose. Patients with Hepatic Impairment Patients with hepatic impairment have reduced clearance of amlodipine with a resulting increase in the AUC of approximately 40-60% [see Dosage and Administration (2.1) ] . Patients with Heart Failure Approximately 40-60% increase in AUC was observed in patients with moderate to severe heart failure. Drug Interaction Studies In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin. Impact of other drugs on amlodipine Co-administered 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 (7.1) ] . Impact of amlodipine on other drugs Amlodipine is a weak inhibitor of CYP3A and may increase exposure to CYP3A substrates. Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time. Simvastatin Co-administration 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 (7.2) ] . 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 (7.2) ] . Tacrolimus A prospective study in healthy Chinese volunteers (N=9) with CYP3A5 expressers showed 2.5- to 4-fold the exposure to tacrolimus when concomitantly administered with amlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressers (N= 6). However, 3-fold the plasma exposure to tacrolimus was seen in a renal transplant patient (CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of post-transplant hypertension. Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excluded with these drugs [see Drug Interactions (7.2) ] .