Norvasc

1 INDICATIONS AND USAGE NORVASC is a calcium channel blocker and may be used alone or in combination with other antihypertensive and antianginal agents for the treatment of: • Hypertension ( 1.1 ) o NORVASC 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. • Coronary Artery Disease ( 1.2 ) o Chronic Stable Angina o Vasospastic Angina (Prinzmetal’s or Variant Angina) o Angiographically Documented Coronary Artery Disease in patients without heart failure or an ejection fraction < 40% 1.1 Hypertension NORVASC ® 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 NORVASC. 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. NORVASC may be used alone or in combination with other antihypertensive agents. 1.2 Coronary Artery Disease (CAD) Chronic Stable Angina NORVASC is indicated for the symptomatic treatment of chronic stable angina. NORVASC may be used alone or in combination with other antianginal agents. Vasospastic Angina (Prinzmetal’s or Variant Angina) NORVASC is indicated for the treatment of confirmed or suspected vasospastic angina. NORVASC 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%, NORVASC 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 once daily with maximum dose 10 mg once daily. ( 2.1 ) o Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily. ( 2.1 ) • Pediatric starting dose: 2.5 mg to 5 mg once daily. ( 2.2 ) Important Limitation : Doses in excess of 5 mg daily have not been studied in pediatric patients. ( 2.2 ) 2.1 Adults The usual initial antihypertensive oral dose of NORVASC is 5 mg once daily, and the maximum dose is 10 mg once daily. Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding NORVASC to other antihypertensive therapy. 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 5–10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect. Coronary artery disease: The recommended dose range for patients with coronary artery disease is 5–10 mg 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 6–17 years is 2.5 mg to 5 mg 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) ] .

3 DOSAGE FORMS AND STRENGTHS Tablets: 2.5 mg white, diamond, flat-faced, beveled edged, with “NORVASC” on one side and “2.5” on the other Tablets: 5 mg white, elongated octagon, flat-faced, beveled edged, engraved with both “NORVASC” and “5” on one side and plain on the other Tablets: 10 mg white, round, flat-faced, beveled edged, engraved with both “NORVASC” and “10” on one side and plain on the other • Tablets: 2.5 mg, 5 mg, and 10 mg ( 3 )

4 CONTRAINDICATIONS NORVASC is contraindicated in patients with known sensitivity to amlodipine. • Known sensitivity to amlodipine ( 4 )

5 WARNINGS AND PRECAUTIONS • Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. However, acute hypotension is unlikely. ( 5.1 ) • Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of NORVASC, particularly in patients with severe obstructive coronary artery disease. ( 5.2 ) • Titrate slowly in patients with severe hepatic impairment. ( 5.3 ) 5.1 Hypotension Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely. 5.2 Increased Angina or Myocardial Infarction Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of NORVASC, particularly in patients with severe obstructive coronary artery disease. 5.3 Patients with Hepatic Failure Because NORVASC is extensively metabolized by the liver and the plasma elimination half‑life (t 1/2 ) is 56 hours in patients with impaired hepatic function, titrate slowly when administering NORVASC to patients with severe hepatic impairment.

6 ADVERSE REACTIONS Most common adverse reaction to amlodipine is edema which occurred in a dose related manner. Other adverse experiences not dose related but reported with an incidence >1.0% are fatigue, nausea, abdominal pain, and somnolence. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Viatris 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. NORVASC has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with NORVASC was well‑tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with NORVASC were of mild or moderate severity. In controlled clinical trials directly comparing NORVASC (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of NORVASC 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 side effects more frequent than placebo are reflected in the table below. The incidence (%) of side effects that occurred in a dose related manner are as follows: Amlodipine Placebo 2.5 mg 5 mg 10 mg N=275 N=296 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 with an incidence greater than 1.0% in placebo‑controlled clinical trials include the following: NORVASC (%) Placebo (%) (N=1730) (N=1250) Fatigue 4.5 2.8 Nausea 2.9 1.9 Abdominal Pain 1.6 0.3 Somnolence 1.4 0.6 For several adverse experiences 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: NORVASC Placebo Male=% Female=% Male=% Female=% (N=1218) (N=512) (N=914) (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 The following events occurred in <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; they are listed to alert the physician to a possible relationship: Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis. Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo. Gastrointestinal: anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia. General: allergic reaction, asthenia, 1 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease. Musculoskeletal System: arthralgia, arthrosis, muscle cramps, 1 myalgia. Psychiatric: sexual dysfunction (male 1 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization. Respiratory System: dyspnea, 1 epistaxis. Skin and Appendages: angioedema, erythema multiforme, pruritus, 1 rash, 1 rash erythematous, rash maculopapular. Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus. Urinary System: micturition frequency, micturition disorder, nocturia. Autonomic Nervous System: dry mouth, sweating increased. Metabolic and Nutritional: hyperglycemia, thirst. Hemopoietic: leukopenia, purpura, thrombocytopenia. 1 These events occurred in less than 1% in placebo‑controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies. NORVASC therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. In the CAMELOT and PREVENT studies [see Clinical Studies (14.4) ] , the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema. 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. The following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, 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. Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine. NORVASC has been used safely in patients with chronic obstructive pulmonary disease, well‑compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

16 HOW SUPPLIED/STORAGE AND HANDLING 2.5 mg Tablets NORVASC – 2.5 mg Tablets (amlodipine besylate equivalent to 2.5 mg of amlodipine per tablet) are supplied as white, diamond, flat‑faced, beveled edged engraved with “NORVASC” on one side and “2.5” on the other side and supplied as follows: NDC 58151-353-77 Bottle of 90 5 mg Tablets NORVASC – 5 mg Tablets (amlodipine besylate equivalent to 5 mg of amlodipine per tablet) are white, elongated octagon, flat‑faced, beveled edged engraved with both “NORVASC” and “5” on one side and plain on the other side and supplied as follows: NDC 58151-354-77 Bottle of 90 NDC 58151-354-88 Unit Dose package of 100 NDC 58151-354-30 Bottle of 300 10 mg Tablets NORVASC – 10 mg Tablets (amlodipine besylate equivalent to 10 mg of amlodipine per tablet) are white, round, flat‑faced, beveled edged engraved with both “NORVASC” and “10” on one side and plain on the other side and supplied as follows: NDC 58151-355-77 Bottle of 90 NDC 58151-355-88 Unit Dose package of 100 Storage Store bottles at controlled room temperature, 59° to 86°F (15° to 30°C) and dispense in tight, light‑resistant containers (USP). Distributed by: Viatris Specialty LLC Morgantown, WV 26505 U.S.A. © 2023 Viatris Inc. NORVASC is a registered trademark of Viatris Specialty LLC, a Viatris Company. UPJ:NRVSCT:R1p Revised: 2/2023