Felodipine Extended-Release Tablets

Description

DESCRIPTION Felodipine is a calcium antagonist (calcium channel blocker). Felodipine is a dihydropyridine derivative that is chemically described as ± ethyl methyl 4-(2,3-dichlorophenyl) -1,4-dihydro-2, 6-dimethyl-3, 5- pyridinedicarboxylate. Its empirical formula is C 18 H 19 Cl 2 NO 4 and its structural formula is: Felodipine is a slightly yellowish, crystalline powder with a molecular weight of 384.26. It is insoluble in water and is freely soluble in dichloromethane and ethanol. Felodipine is a racemic mixture. Felodipine Extended-release Tablets, USP provide extended release of felodipine. They are available as tablets containing 2.5 mg, 5 mg, or 10 mg of felodipine for oral administration. Inactive ingredients for core tablets are: anhydrous lactose, butylated hydroxyanisole, butylated hydroxytoluene, colloidal silicon dioxide, hypromellose, polyoxyl 40 hydrogenated castor oil, microcrystalline cellulose, povidone K30 and sodium stearyl fumarate. Film coating materials of 2.5mg: ferrosoferric oxide, hypromellose, iron oxide red, iron oxide yellow, maltodextrin, medium chain triglycerides, polydextrose, talc and titanium dioxide. Film coating materials of 5mg: ferrosoferric oxide, hypromellose, iron oxide red, iron oxide yellow, maltodextrin, medium chain triglycerides, polydextrose, talc and titanium dioxide. Film coating materials of 10mg: ferrosoferric oxide, hypromellose, iron oxide red, iron oxide yellow, maltodextrin, medium chain triglycerides, polydextrose, talc and titanium dioxide. Chemical Structure

What Is Felodipine Extended-Release Tablets Used For?

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 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.

Dosage and Administration

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 2.5–10 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 should regularly be taken either without food or with a light meal (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism ). Felodipine 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; therefore, patients should have their blood pressure monitored closely during dosage adjustment of Felodipine (see CLINICAL PHARMACOLOGY ).

Side Effects (Adverse Reactions)

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 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, 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, 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 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 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 (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. 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 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) Adverse events that occurred in 0.5 up to 1.5% of patients who received Felodipine 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 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...

Drug Interactions

Drug Interactions CYP3A4 Inhibitors —Felodipine is metabolized by CYP3A4. Co-administration of CYP3A4 inhibitors (eg, 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 Cmax, 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 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 the pharmacokinetics of digoxin in patients with heart failure was 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...

Contraindications

CONTRAINDICATIONS Felodipine is contraindicated in patients who are hypersensitive to this product.

Pregnancy and Breastfeeding

Pregnancy Pregnancy Category C. Teratogenic Effects : 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/m 2 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. 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/m 2 basis). This effect occurred only in pregnant rabbits and regressed during lactation. ** Based on patient weight of 50 kg 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 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.

Overdosage

OVERDOSAGE Oral doses of 240 mg/kg and 264 mg/kg in male and female mice, respectively, and 2390 mg/kg and 2250 mg/kg in male and female rats, respectively, caused significant lethality. In a suicide attempt, one patient took 150 mg felodipine together with 15 tablets each of atenolol and spironolactone and 20 tablets of nitrazepam. The patient's blood pressure and heart rate were normal on admission to hospital; he subsequently recovered without significant sequelae. Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly bradycardia. If severe hypotension occurs, symptomatic treatment should be instituted. The patient should be placed supine with the legs elevated. The administration of intravenous fluids may be useful to treat hypotension due to overdosage with calcium antagonists. In case of accompanying bradycardia, atropine (0.5–1 mg) should be administered intravenously. Sympathomimetic drugs may also be given if the physician feels they are warranted. It has not been established whether felodipine can be removed from the circulation by hemodialysis. To obtain up-to-date information about the treatment of overdose, consult your Regional Poison-Control Center. Telephone numbers of certified poison-control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient.

How Supplied

HOW SUPPLIED Felodipine Extended-release Tablets, USP 2.5 mg, are yellow film-coated, round convex tablets, with code Y161 on one side. They are supplied as follows: NDC 69117-0028-1 bottles of 100 NDC 69117-0028-2 bottles of 500 Felodipine Extended-release Tablets, USP 5 mg, are pink film-coated, round convex tablets, with code Y162 on one side. They are supplied as follows: NDC 69117-0029-1 bottles of 100’s NDC 69117-0029-2 bottles of 500’s Felodipine Extended-release Tablets, USP 10 mg, are red film-coated, round convex tablets, with code Y163 on one side. They are supplied as follows: NDC 69117-0030-1 bottles of 100’s NDC 69117-0030-2 bottles of 500’s Storage: Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from light. Manufacturer: Yiling Pharmaceutical Ltd No. 36 Zhujiang Road, Shijiazhuang, Hebei, 050035, China Distributor: Yiling Pharmaceutical, Inc. 5348 Vegas Drive, Las Vegas, NV 89108, USA Revised: 07/2018