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FELODIPINE (Tablet, Film Coated, Extended Release)

Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1850

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FELODIPINE (Tablet, Film Coated, Extended Release)
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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 anincreased blood pressure response but a large increase in the rate of peripheral edema and other vasodilatory adverse events . 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 . Felodipine should be swallowed whole and not crushed or chewed.<br/>Geriatric Use: Patients over 65 years of age are likely to develop higher plasma concentrations of felodipine . 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.<br/>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 .
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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 molecular formula is CHClNOand 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 tablets provide extended release of felodipine. They are available as tablets containing 2.5 mg, 5 mg, or 10 mg of felodipine for oral administration. In addition to the active ingredient felodipine, the tablets contain the following inactive ingredients: felodipine tablets 2.5 mg���carnauba wax, hypromellose, hydroxypropyl cellulose, microcrystalline cellulose, polyethylene glycol, povidone, silicon dioxide, titanium dioxide, D&C Yellow #10 Lake, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake. Felodipine tablets 5 mg���carnauba wax, hypromellose, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, silicon dioxide, titanium dioxide, FD&C Red No. 40 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake. Felodipine tablets 10 mg���carnauba wax, hypromellose, hydroxypropyl cellulose, microcrystalline cellulose, polyethylene glycol, povidone, silicon dioxide, titanium dioxide, D&C Yellow #10 Lake, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake. The USP drug release Test # is pending.
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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.<br/>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 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. Following oral administration of the immediate-release formulation, the plasma level of felodipine also declined polyexponentially with a mean terminal tof 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) [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 were 23 and 7 nmol/L. Since the EC50 for felodipine is 4 to 6 nmol/L, a 5- to 10-mg dose of felodipine in some patients, and a 20-mg dose in others, would be expected to provide an antihypertensive effect that persists for 24 hours . 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 ofC-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 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 is influenced by the presence of food. When administered either with a high fat or carbohydrate diet, Cis increased by approximately 60%; AUC is unchanged. When felodipine was 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. A similar finding has been seen with other dihydropyridine calcium antagonists, but to a lesser extent than that seen with felodipine.<br/>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.<br/>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.<br/>Cardiovascular Effects: Following administration of felodipine, 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 .<br/>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.<br/>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 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 given once daily as monotherapy are shown inthe table below:
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Felodipine is contraindicated in patients who are hypersensitive to this product.
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FELODIPINE EXTENDED-RELEASE TABLETS are supplied as follows: Felodipine extended-release tablets, 2.5 mg, round, light green, film-coated, unscored, debossed MP 771Bottles of 30 NDC 53489-368-07Bottles of 90 NDC 53489-368-90Bottles of 100 NDC 53489-368-01Bottles of 250 NDC 53489-368-03Bottles of 500 NDC 53489-368-05Bottles of 1000 NDC 53489-368-10 Felodipine extended-release tablets, 5 mg, round, light orange, film-coated, unscored, debossed MP 772Bottles of 30 NDC 53489-369-07Bottles of 90 NDC 53489-369-90Bottles of 100 NDC 53489-369-01Bottles of 250 NDC 53489-369-03Bottles of 500 NDC 53489-369-05Bottles of 1000 NDC 53489-369-10 Felodipine extended-release tablets, 10 mg, round, brown, film-coated, unscored, debossed MP 773Bottles of 30 NDC 53489-370-07Bottles of 90 NDC 53489-370-90Bottles of 100 NDC 53489-370-01Bottles of 250 NDC 53489-370-03Bottles of 500 NDC 53489-370-05Bottles of 1000 NDC 53489-370-10 Store at 20��to 25��C (68��to 77��F). [See USP Controlled Room Temperature] PROTECT FROM LIGHT DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER
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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.
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felodipine
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FELODIPINE (Tablet, Film Coated, Extended Release)
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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 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 offelodipine 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 . 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 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.<br/>Clinical Laboratory Test Findings: Serum Electrolytes���No significant effects on serum electrolytes were observed during short- and long-term therapy . Serum Glucose���No significant effects on fasting serum glucose were observed in patients treated with felodipine 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.
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Felodipine is indicated for the treatment of hypertension. Felodipine may be used alone or concomitantly with other antihypertensive agents.
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FELODIPINE