Felodipine

Mechanism of Action Felodipine is a member of the dihydropyridine class of calcium channel antagonists (calcium channel blockers). It reversibly competes with nitrendipine and/or other calcium channel blockers for dihydropyridine binding sites, blocks voltage-dependent Ca ++ currents in vascular smooth muscle and cultured rabbit atrial cells, and blocks potassium-induced contracture of the rat portal vein. In vitro studies show that the effects of felodipine on contractile processes are selective, with greater effects on vascular smooth muscle than cardiac muscle. Negative inotropic effects can be detected in vitro , but such effects have not been seen in intact animals. The effect of felodipine on blood pressure is principally a consequence of a dose-related decrease of peripheral vascular resistance in man, with a modest reflex increase in heart rate (see Cardiovascular Effects ). With the exception of a mild diuretic effect seen in several animal species and man, the effects of felodipine are accounted for by its effects on peripheral vascular resistance.

INDICATIONS AND USAGE Felodipine extended-release tablets, USP are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal 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 felodipine. 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

DOSAGE AND ADMINISTRATION The recommended starting dose is 5 mg once a day. Depending on the patient's response, the dosage can be decreased to 2.5 mg or increased to 10 mg once a day. These adjustments should occur generally at intervals of not less than 2 weeks. The recommended dosage range is 2.5 to 10 mg once daily. In clinical trials, doses above 10 mg daily showed an increased blood pressure response but a large increase in the rate of peripheral edema and other vasodilatory adverse events (see ADVERSE REACTIONS ). Modification of the recommended dosage is usually not required in patients with renal impairment. Felodipine extended-release tablets, USP should regularly be taken either without food or with a light meal (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism ). Felodipine extended-release tablets, USP should be swallowed whole and not crushed or chewed. Geriatric Use Patients over 65 years of age are likely to develop higher plasma concentrations of felodipine (see CLINICAL 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, USP; therefore, patients should have their blood pressure monitored closely during dosage adjustment of felodipine extended-release tablets, USP (see CLINICAL PHARMACOLOGY ).

ADVERSE REACTIONS In controlled studies in the United States and overseas, approximately 3000 patients were treated with felodipine as either the extended-release or the immediate-release formulation. The most common clinical adverse events reported with felodipine extended-release administered as monotherapy at the recommended dosage range of 2.5 mg to 10 mg once a day were peripheral edema and headache. Peripheral edema was generally mild, but it was age and dose related and resulted in discontinuation of therapy in about 3% of the enrolled patients. Discontinuation of therapy due to any clinical adverse event occurred in about 6% of the patients receiving felodipine extended-release, principally for peripheral edema, headache, or flushing. Adverse events that occurred with an incidence of 1.5% or greater at any of the recommended doses of 2.5 mg to 10 mg once a day (felodipine extended-release, N = 861; Placebo, N = 334), without regard to causality, are compared to 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, USP 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, USP 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) *Patients in titration studies may have been exposed to more than one dose level of felodipine extended-release tablets. 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) 2.0 (0) 8.8 (2.2) 17.4 (2.5) Asthenia 3.3 (0) 3.9 (0) 3.3 (0) 2.2 (0) Warm Sensation 0 (0) 0 (0) 0.9 (0.2) 1.5 (0) Cardiovascular Palpitation 2.4 (0) 0.4 (0) 1.4 (0.3) 2.5 (0.5) Digestive Nausea 1.5 (0.9) 1.2 (0) 1.7 (0.3) 1 (0.7) Dyspepsia 1.2 (0) 3.9 (0) 0.7 (0) 0.5 (0) Constipation 0.9 (0) 1.2 (0) 0.3 (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) 3.6 (0.5) 3.7 (0.5) Paresthesia 1.5 (0.3) 1.6 (0) 1.2 (0) 1.2 (0.2) Respiratory Upper Respiratory Infection 1.8 (0) 3.9 (0) 1.9 (0) 0.7 (0) Cough 0.3 (0) 0.8 (0) 1.2 (0) 1.7 (0) Rhinorrhea 0 (0) 1.6 (0) 0.2 (0) 0.2 (0) Sneezing 0 (0) 1.6 (0) 0 (0) 0 (0) Skin Rash 0.9 (0) 2 (0) 0.2 (0) 0.2 (0) Flushing 0.9 (0.3) 3.9 (0) 5.3 (0.7) 6.9 (1.2) Adverse events that occurred in 0.5% up to 1.5% of patients who received felodipine extended-release 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 is 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 in the U.S. controlled study. Liver Enzymes One of two episodes of elevated serum transaminases decreased once drug was discontinued in clinical studies; no follow-up was available for the other patient.

Drug Interactions CYP3A4 Inhibitors Felodipine is metabolized by CYP3A4. Co-administration of CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin, grapefruit juice, cimetidine) with felodipine may lead to several-fold increases in the plasma levels of felodipine, either due to an increase in bioavailability or due to a decrease in metabolism. These increases in concentration may lead to increased effects, (lower blood pressure and increased heart rate). These effects have been observed with co-administration of itraconazole (a potent CYP3A4 inhibitor). Caution should be used when CYP3A4 inhibitors are co-administered with felodipine. A conservative approach to dosing felodipine should be taken. The following specific interactions have been reported: Itraconazole Co-administration of another extended release formulation of felodipine with itraconazole resulted in approximately 8-fold increase in the AUC, more than 6-fold increase in the C max , and 2-fold prolongation in the half-life of felodipine. Erythromycin Co-administration of felodipine with erythromycin resulted in approximately 2.5-fold increase in the AUC and C max , and about 2-fold prolongation in the half-life of felodipine. Grapefruit Juice Co-administration of felodipine with grapefruit juice resulted in more than 2-fold increase in the AUC and C max , but no prolongation in the half-life of felodipine. Cimetidine Co-administration of felodipine with cimetidine (a non-specific CYP-450 inhibitor) resulted in an increase of approximately 50% in the AUC and the C max , of felodipine. Beta-Blocking Agents A pharmacokinetic study of felodipine in conjunction with metoprolol demonstrated no significant effects on the pharmacokinetics of felodipine. The AUC and C max of metoprolol, however, were increased approximately 31 and 38%, respectively. In controlled clinical trials, however, beta-blockers including metoprolol were concurrently administered with felodipine and were well tolerated. Digoxin When given concomitantly with felodipine extended-release the pharmacokinetics of digoxin in patients with heart failure were not significantly altered. Anticonvulsants In a pharmacokinetic study, maximum plasma concentrations of felodipine were considerably lower in epileptic patients on long-term anticonvulsant therapy (e.g., phenytoin, carbamazepine, or phenobarbital) than in healthy volunteers. In such patients, the mean area under the felodipine plasma concentration-time curve was also reduced to approximately 6% of that observed in healthy volunteers. Since a clinically significant interaction may be anticipated, alternative antihypertensive therapy should be considered in these patients. Tacrolimus Felodipine may increase the blood concentration of tacrolimus. When given concomitantly with felodipine, the tacrolimus blood concentration should be followed and the tacrolimus dose may need to be adjusted. Other Concomitant Therapy In healthy subjects there were no clinically significant interactions when felodipine was given concomitantly with indomethacin or spironolactone. Interaction with Food see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism .