Plendil Information
Plendil (Felodipine) Description
Plendil (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 CHClNO 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.
Tablets Plendil (Felodipine) 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: Tablets Plendil (Felodipine) 2.5 mg — hydroxypropyl cellulose, lactose, FD&C Blue 2, sodium stearyl fumarate, titanium dioxide, yellow iron oxide, and other ingredients. Tablets Plendil (Felodipine) 5 mg and 10 mg — cellulose, red and yellow oxide, lactose, polyethylene glycol, sodium stearyl fumarate, titanium dioxide, and other ingredients.
Plendil (Felodipine) Clinical Pharmacology
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 Cacurrents in vascular smooth muscle and cultured rabbit atrial cells, and blocks potassium-induced contracture of the rat portal vein.
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.
Following oral administration, felodipine is almost completely absorbed and undergoes extensive first-pass metabolism. The systemic bioavailability of Plendil (Felodipine) is approximately 20%. Mean peak concentrations following the administration of Plendil (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 Plendil (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 Plendil (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 Plendil (Felodipine) 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 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 (
Following administration of Plendil (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 Plendil (Felodipine) is influenced by the presence of food. When administered either with a high fat or carbohydrate diet, C is increased by approximately 60%; AUC is unchanged. When Plendil (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 Plendil (Felodipine) . A similar finding has been seen with other dihydropyridine calcium antagonists, but to a lesser extent than that seen with felodipine.
Geriatric Use
Hepatic Dysfunction
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.
Following administration of Plendil (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 (see PRECAUTIONS).
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.
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 Plendil (Felodipine) given once daily as monotherapy are shown in the table below:
MEAN REDUCTIONS IN BLOOD PRESSURE (mmHg)
Plendil (Felodipine) Indications And Usage
Plendil (Felodipine) is indicated for the treatment of hypertension.
Plendil (Felodipine) may be used alone or concomitantly with other antihypertensive agents.
Plendil (Felodipine) Contraindications
Plendil (Felodipine) is contraindicated in patients who are hypersensitive to this product.
Plendil (Felodipine) Precautions
Hypotension
Heart Failure
Patients with Impaired Liver Function
Peripheral Edema
Patients should be instructed to take Plendil (Felodipine) whole and not to crush or chew the tablets. They should be told that mild gingival hyperplasia (gum swelling) has been reported. Good dental hygiene decreases its incidence and severity.
NOTE: As with many other drugs, certain advice to patients being treated with Plendil (Felodipine) is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
CYP3A4 Inhibitors
Itraconazole
max
Erythromycin
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Grapefruit juice
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Cimetidine
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Beta-Blocking Agents
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Digoxin
Anticonvulsants
Tacrolimus
Other Concomitant Therapy
Interaction with Food
In a 2-year carcinogenicity study in rats fed felodipine at doses of 7.7, 23.1 or 69.3 mg/kg/day (up to 61 times the maximum recommended human dose on a mg/m basis), a dose-related increase in the incidence of benign interstitial cell tumors of the testes (Leydig cell tumors) was observed in treated male rats. These tumors were not observed in a similar study in mice at doses up to 138.6 mg/kg/day (61 times the maximum recommended human dose on a mg/m basis). Felodipine, at the doses employed in the 2-year rat study, has been shown to lower testicular testosterone and to produce a corresponding increase in serum luteinizing hormone in rats. The Leydig cell tumor development is possibly secondary to these hormonal effects which have not been observed in man.
In this same rat study a dose-related increase in the incidence of focal squamous cell hyperplasia compared to control was observed in the esophageal groove of male and female rats in all dose groups. No other drug-related esophageal or gastric pathology was observed in the rats or with chronic administration in mice and dogs. The latter species, like man, has no anatomical structure comparable to the esophageal groove.
Felodipine was not carcinogenic when fed to mice at doses up to 138.6 mg/kg/day (61 times the maximum recommended human dose on a mg/m basis) for periods of up to 80 weeks in males and 99 weeks in females.
Felodipine did not display any mutagenic activity in the Ames microbial mutagenicity test or in the mouse lymphoma forward mutation assay. No clastogenic potential was seen in the mouse micronucleus test at oral doses up to 2500 mg/kg (1100 times the maximum recommended human dose on a mg/m basis) or in a human lymphocyte chromosome aberration assay.
A fertility study in which male and female rats were administered doses of 3.8, 9.6 or 26.9 mg/kg/day (up to 24 times the maximum recommended human dose on a mg/mbasis) showed no significant effect of felodipine on reproductive performance.
Plendil (Felodipine) 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 Plendil (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 Plendil (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 (Plendil (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 Plendil (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 Plendil (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).
Adverse events that occurred in 0.5 up to 1.5% of patients who received Plendil (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 Plendil (Felodipine) is uncertain: Chest pain, facial edema, flu-like illness; , , tachycardia, premature beats; Abdominal pain, diarrhea, vomiting, dry mouth, flatulence, acid regurgitation; Gynecomastia; ; ALT (SGPT) increased; Arthralgia, back pain, leg pain, foot pain, muscle cramps, myalgia, arm pain, knee pain, hip pain; Insomnia, depression, anxiety disorders, irritability, nervousness, somnolence, decreased libido; Dyspnea, pharyngitis, bronchitis, influenza, sinusitis, epistaxis, respiratory infection; contusion, erythema, urticaria; Visual disturbances; Impotence, urinary frequency, urinary urgency, dysuria, polyuria.
Plendil (Felodipine) 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 . In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient.
Plendil (Felodipine) 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.
Plendil (Felodipine) should regularly be taken either without food or with a light meal (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism). Plendil (Felodipine) should be swallowed whole and not crushed or chewed.
Plendil (Felodipine) How Supplied
No. 3584 — Tablets Plendil (Felodipine) , 2.5 mg, are sage green, round convex tablets, with code 450 on one side and Plendil (Felodipine) on the other. They are supplied as follows:
NDC 0186-0450-58 unit of use bottles of 100
No. 3585 — Tablets Plendil (Felodipine) , 5 mg, are light red-brown, round convex tablets, with code 451 on one side and Plendil (Felodipine) on the other. They are supplied as follows:
NDC 0186-0451-58 unit of use bottles of 100
No. 3586 — Tablets Plendil (Felodipine) , 10 mg, are red-brown, round convex tablets, with code 452 on one side and Plendil (Felodipine) on the other. They are supplied as follows:
NDC 0186-0452-58 unit of use bottles of 100
