e 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 (eg, on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. felodipine extended-release tablets, usp may be administered with other antihypertensive agents.

l pharmacology ). in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range (2.5 mg daily). elderly patients should have their blood pressure closely monitored during any dosage adjustment. patients with impaired liver function - patients with impaired liver function may have elevated plasma concentrations of felodipine and may respond to lower doses of felodipine extended-release tablets; therefore, patients should have their blood pressure monitored closely during dosage adjustment of felodipine extended-release tablets (see clinical pharmacology ).

placebo and are listed by dose in the table below. these events are reported from controlled clinical trials with patients who were randomized to a fixed dose of felodipine extended-release tablets or titrated from an initial dose of 2.5 mg or 5 mg once a day. a dose of 20 mg once a day has been evaluated in some clinical studies. although the antihypertensive effect of felodipine extended-release tablets is increased at 20 mg once a day, there is a disproportionate increase in adverse events, especially those associated with vasodilatory effects (see dosage and administration ). percent of patients with adverse events in controlled trials* of felodipine extended-release tablets (n = 861) as monotherapy without regard to causality (incidence of discontinuations shown in parentheses) body system adverse events placebo n=334 2.5 mg n=255 5 mg n=581 10 mg n= 408 body as a whole peripheral edema 3.3 (0.0) 2.0 (0.0) 8.8 (2.2) 17.4 (2.5) asthenia 3.3 (0.0) 3.9 (0.0) 3.3 (0.0) 2.2 (0.0) warm sensation 0.0 (0.0) 0.0 (0.0) 0.9 (0.2) 1.5 (0.0) cardiovascular palpitation 2.4 (0.0) 0.4 (0.0) 1.4 (0.3) 2.5 (0.5) digestive nausea 1.5 (0.9) 1.2 (0.0) 1.7 (0.3) 1.0 (0.7) dyspepsia 1.2 (0.0) 3.9 (0.0) 0.7 (0.0) 0.5 (0.0) constipation 0.9 (0.0) 1.2 (0.0) 0.3 (0.0) 1.5 (0.2) nervous headache 10.2 (0.9) 10.6 (0.4) 11.0 (1.7) 14.7 (2.0) dizziness 2.7 (0.3) 2.7 (0.0) 3.6 (0.5) 3.7 (0.5) paresthesia 1.5 (0.3) 1.6 (0.0) 1.2 (0.0) 1.2 (0.2) respiratory upper respiratory infection 1.8 (0.0) 3.9 (0.0) 1.9 (0.0) 0.7 (0.0) cough 0.3 (0.0) 0.8 (0.0) 1.2 (0.0) 1.7 (0.0) rhinorrhea 0.0 (0.0) 1.6 (0.0) 0.2 (0.0) 0.2 (0.0) sneezing 0.0 (0.0) 1.6 (0.0) 0.0 (0.0) 0.0 (0.0) skin rash 0.9 (0.0) 2.0 (0.0) 0.2 (0.0) 0.2 (0.0) flushing 0.9 (0.3) 3.9 (0.0) 5.3 (0.7) 6.9 (1.2) *patients in titration studies may have been exposed to more than one level of felodipine extended-release tablets. adverse events that occurred in 0.5% up to 1.5% of patients who received felodipine extended-release tablets in all controlled clinical trials at the recommended dosage range of 2.5 mg to 10 mg once a day, and serious adverse events that occurred at a lower rate, or events reported during marketing experience (those lower rate events are in italics) are listed below. these events are listed in order of decreasing severity within each category, and the relationship of these events to administration of felodipine extended-release tablets are uncertain: body as a whole : chest pain, facial edema, flu-like illness cardiovascular : myocardial infarction, hypotension, syncope, angina pectoris , arrhythmia , tachycardia, premature beats; digestive: abdominal pain, diarrhea, vomiting, dry mouth, flatulence, acid regurgitation endocrine: gynecomastia hematologic: anemia metabolic : alt (sgpt) increased musculoskeletal: arthralgia, back pain, leg pain, foot pain, muscle cramps, myalgia, arm pain, knee pain, hip pain nervous/psychiatric : insomnia, depression, anxiety disorders, irritability, nervousness, somnolence, decreased libido respiratory : dyspnea, pharyngitis, bronchitis, influenza, sinusitis, epistaxis, respiratory infection skin : angioedema, contusion, erythema, urticaria , leukocytoclastic vasculitis special senses : visual disturbances urogenital : impotence, urinary frequency, urinary urgency, dysuria, polyuria. gingival hyperplasia : gingival hyperplasia, usually mild, occurred in < 0.5% of patients in controlled studies. this condition may be avoided or may regress with improved dental hygiene. (see precautions, information for patients .) clinical laboratory test findings serum electrolytes - no significant effects on serum electrolytes were observed during short- and long-term therapy (see clinical pharmacology:renal/endocrine effects ). serum glucose - no significant effects on fasting serum glucose were observed in patients treated with felodipine extended-release tablets in the u.s. controlled study. liver enzymes - 1 of 2 episodes of elevated serum transaminases decreased once drug was discontinued in clinical studies; no follow-up was available for the other patient. to report suspected adverse reactions, contact avet pharmaceuticals inc. at 1-866-901-drug (3784) or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

, the effects of felodipine are accounted for by its effects on peripheral vascular resistance. pharmacokinetics and metabolism following oral administration, felodipine is almost completely absorbed and undergoes extensive first-pass metabolism. the systemic bioavailability of felodipine is approximately 20%. mean peak concentrations following the administration of felodipine extended-release tablets are reached in 2.5 to 5 hours. both peak plasma concentration and the area under the plasma concentration time curve (auc) increase linearly with doses up to 20 mg. felodipine is greater than 99% bound to plasma proteins. following intravenous administration, the plasma concentration of felodipine declined triexponentially with mean disposition half-lives of 4.8 minutes, 1.5 hours, and 9.1 hours. the mean contributions of the three individual phases to the overall auc were 15, 40 and 45%, respectively, in the order of increasing t 1/2 . following oral administration of the immediate-release formulation, the plasma level of felodipine also declined polyexponentially with a mean terminal t 1/2 of 11 to 16 hours. the mean peak and trough steady-state plasma concentrations achieved after 10 mg of the immediate-release formulation given once a day to normal volunteers, were 20 and 0.5 nmol/l, respectively. the trough plasma concentration of felodipine in most individuals was substantially below the concentration needed to effect a half-maximal decline in blood pressure (ec 50 ) [4 - 6 nmol/l for felodipine], thus precluding once-a-day dosing with the immediate-release formulation. following administration of a 10-mg dose of felodipine, the extended-release formulation, to young, healthy volunteers, mean peak and trough steady-state plasma concentrations of felodipine were 7 and 2 nmol/l, respectively. corresponding values in hypertensive patients (mean age 64) after a 20-mg dose of felodipine extended-release tablets were 23 and 7 nmol/l. since the ec 50 for felodipine is 4 to 6 nmol/l, a 5 mg to 10 mg dose of felodipine extended-release tablets in some patients, and a 20 mg dose in others, would be expected to provide an antihypertensive effect that persists for 24 hours (see cardiovascular effects below and dosage and administration ). the systemic plasma clearance of felodipine in young healthy subjects is about 0.8 l/min, and the apparent volume of distribution is about 10 l/kg. following an oral or intravenous dose of 14 c-labeled felodipine in man, about 70% of the dose of radioactivity was recovered in urine and 10% in the feces. a negligible amount of intact felodipine is recovered in the urine and feces (< 0.5%). six metabolites, which account for 23% of the oral dose, have been identified; none has significant vasodilating activity. following administration of felodipine extended-release tablets to hypertensive patients, mean peak plasma concentrations at steady state are about 20% higher than after a single dose. blood pressure response is correlated with plasma concentrations of felodipine. the bioavailability of felodipine extended-release tablets are influenced by the presence of food. when administered either with a high fat or carbohydrate diet, c max is increased by approximately 60%; auc is unchanged. when felodipine extended-release tablets were administered after a light meal (orange juice, toast, and cereal), however, there is no effect on felodipine's pharmacokinetics. the bioavailability of felodipine was increased approximately two-fold when taken with grapefruit juice. orange juice does not appear to modify the kinetics of felodipine extended-release tablets. a similar finding has been seen with other dihydropyridine calcium antagonists, but to a lesser extent than that seen with felodipine. geriatric use - plasma concentrations of felodipine, after a single dose and at steady state, increase with age. mean clearance of felodipine in elderly hypertensives (mean age 74) was only 45% of that of young volunteers (mean age 26). at steady state mean auc for young patients was 39% of that for the elderly. data for intermediate age ranges suggest that the aucs fall between the extremes of the young and the elderly. hepatic dysfunction - in patients with hepatic disease, the clearance of felodipine was reduced to about 60% of that seen in normal young volunteers. renal impairment does not alter the plasma concentration profile of felodipine; although higher concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these are inactive. animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta. cardiovascular effects following administration of felodipine extended-release tablets, a reduction in blood pressure generally occurs within 2 to 5 hours. during chronic administration, substantial blood pressure control lasts for 24 hours, with trough reductions in diastolic blood pressure approximately 40 - 50% of peak reductions. the antihypertensive effect is dose dependent and correlates with the plasma concentration of felodipine. a reflex increase in heart rate frequently occurs during the first week of therapy; this increase attenuates over time. heart rate increases of 5 - 10 beats per minute may be seen during chronic dosing. the increase is inhibited by beta-blocking agents. the p-r interval of the ecg is not affected by felodipine when administered alone or in combination with a beta-blocking agent. felodipine alone or in combination with a beta-blocking agent has been shown, in clinical and electrophysiologic studies, to have no significant effect on cardiac conduction (p-r, p-q, and h-v intervals). in clinical trials in hypertensive patients without clinical evidence of left ventricular dysfunction, no symptoms suggestive of a negative inotropic effect were noted; however, none would be expected in this population (see precautions). renal/endocrine effects renal vascular resistance is decreased by felodipine while glomerular filtration rate remains unchanged. mild diuresis, natriuresis, and kaliuresis have been observed during the first week of therapy. no significant effects on serum electrolytes were observed during short- and long-term therapy. in clinical trials in patients with hypertension, increases in plasma noradrenaline levels have been observed. clinical studies felodipine produces dose-related decreases in systolic and diastolic blood pressure as demonstrated in six placebo-controlled, dose response studies using either immediate-release or extended-release dosage forms. these studies enrolled over 800 patients on active treatment, at total daily doses ranging from 2.5 mg to 20 mg. in those studies felodipine was administered either as monotherapy or was added to beta blockers. the results of the 2 studies with felodipine extended-release tablets given once daily as monotherapy are shown in the table below: mean reductions in blood pressure (mmhg) placebo response subtracted. dose n systolic/diastolic mean peak response mean trough response trough/peak ratios (% s ) study 1 (8 weeks) 2.5 mg 68 9.4/4.7 2.7/2.5 29/53 5 mg 69 9.5/6.3 2.4/3.7 25/59 10 mg 67 18.0/10.8 10.0/6.0 56/56 study 2 (4 weeks) 10 mg 50 5.3/7.2 1.5/3.2 33/40 different number of patients available for peak and trough measurements. 50 11.3/10.2 4.5/3.2 43/34

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