Felodipine

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 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 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 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. Felodipine extended-release tablets, USP may be administered with other antihypertensive agents.

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 mg 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 should regularly be taken either without food or with a light meal (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism ). Felodipine extended-release tablets 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; therefore, patients should have their blood pressure monitored closely during dosage adjustment of felodipine extended-release tablets (see CLINICAL PHARMACOLOGY ).

CONTRAINDICATIONS Felodipine extended-release tablets are contraindicated in patients who are hypersensitive to this product.

Drug Interactions CYP3A4 Inhibitors Felodipine is metabolized by CYP3A4. Coadministration 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 coadministration of itraconazole (a potent CYP3A4 inhibitor). Caution should be used when CYP3A4 inhibitors are coadministered with felodipine. A conservative approach to dosing felodipine should be taken. The following specific interactions have been reported: Itraconazole Coadministration 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 Cmax, and 2-fold prolongation in the half-life of felodipine. Erythromycin Coadministration of felodipine extended-release tablets with erythromycin resulted in approximately 2.5-fold increase in the AUC and Cmax, and about 2-fold prolongation in the half-life of felodipine. Grapefruit Juice Coadministration of felodipine extended-release tablets with grapefruit juice resulted in more than 2-fold increase in the AUC and Cmax, but no prolongation in the half-life of felodipine. Cimetidine Coadministration of felodipine with cimetidine (a non-specific CYP-450 inhibitor) resulted in an increase of approximately 50% in the AUC and the Cmax, 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 Cmax 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 tablets 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 .

Pregnancy Teratogenic Effects. Pregnancy Category C Studies in pregnant rabbits administered doses of 0.46, 1.2, 2.3 and 4.6 mg/kg/day (from 0.8 to 8 times** the maximum recommended human dose on a mg/m2 basis) showed digital anomalies consisting of reduction in size and degree of ossification of the terminal phalanges in the fetuses. The frequency and severity of the changes appeared dose related and were noted even at the lowest dose. These changes have been shown to occur with other members of the dihydropyridine class and are possibly a result of compromised uterine blood flow. Similar fetal anomalies were not observed in rats given felodipine. In a teratology study in cynomolgus monkeys, no reduction in the size of the terminal phalanges was observed, but an abnormal position of the distal phalanges was noted in about 40% of the fetuses. Nonteratogenic Effects A prolongation of parturition with difficult labor and an increased frequency of fetal and early postnatal deaths were observed in rats administered doses of 9.6 mg/kg/day (8 times** the maximum human dose on a mg/m2 basis) and above. **Based on patient weight of 50 kg Significant enlargement of the mammary glands, in excess of the normal enlargement for pregnant rabbits, was found with doses greater than or equal to 1.2 mg/kg/day (2.1 times the maximum human dose on a mg/m2 basis). This effect occurred only in pregnant rabbits and regressed during lactation. Similar changes in the mammary glands were not observed in rats or monkeys. There are no adequate and well controlled studies in pregnant women. If felodipine extended-release tablet is used during pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus, possible digital anomalies of the infant, and the potential effects of felodipine on labor and delivery and on the mammary glands of pregnant females.

Nursing Mothers It is not known whether this drug is secreted in human milk and because of the potential for serious adverse reactions from felodipine in the infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

ADVERSE REACTIONS In controlled studies in the United States and overseas, approximately 3,000 patients were treated with felodipine as either the extended-release or the immediate-release formulation. The most common clinical adverse events reported with felodipine extendedrelease tablets 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 tablets, 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 extendedrelease tablets, 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 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 ). 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 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 tablets 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.