Information for the Patient
Plendil
Pharmacology
Felodipine is completely absorbed from the gastrointestinal tract after oral administration. Due to rapid biotransformation of felodipine during its first pass through the portal circulation, the systemic availability is approximately 15% and is independent of the dose in the range of 5 to 20 mg/day. The plasma protein binding of felodipine is approximately 99%. It is bound predominately to the albumin fraction.
Felodipine is extensively metabolized by the liver, predominantly by cytochrome P450 CYP 3A4. After 72 hours, approximately 70% of a given dose is excreted as metabolites in the urine and 10% is secreted in the feces. Less than 0.5% of a dose is recovered unchanged in the urine. Six metabolites, which account for 23% of the oral dose, have been identified: none has significant vasodilating activity.
Felodipine has been observed to have a mean blood clearance of 914±355 mL/min in hypertensive patients, 606±245 mL/min in elderly hypertensive patients and 1337±413 mL/min in young healthy volunteers. Its mean terminal half-life was 24.5±7.0 hours in hypertensive patients, 27.5±8.4 hours in elderly hypertensive patients and 14.1±5.6 hours in young healthy volunteers.
The extended release formulation prolongs the absorption phase of felodipine resulting in an increased time to reach peak plasma concentrations (tmax), and a reduced maximum plasma concentration (Cmax). The mean tmax ranges from 2.5 to 5 hours. The area under the plasma concentration versus time curve and Cmax are linearly related to the dose in the 10 to 40 mg range. Following administration of felodipine to hypertensive patients, mean Cmax at steady state is approximately 20% higher after multiple doses than after a single dose. No increase in the AUC is found during multiple dosing. The inter-individual variation in Cmax and AUC after repeated dosing is approximately 3-fold and indicates a need for individualized dosing.
The bioavailability of felodipine is not influenced by the presence of food in the gastrointestinal tract. However, the peak plasma concentration of felodipine (Cmax) is significantly increased by 1.5- to 2-fold when felodipine is taken after a high fat or high carbohydrate meal versus fasting. Because the effects of felodipine on blood pressure are related to plasma levels, this increase in Cmax may cause a clinically significant fall in blood pressure. Therefore felodipine should not be administered with meals rich in carbohydrate or fat. However, the absorption characteristics of felodipine are not affected when felodipine is administered with a light meal low in fat and carbohydrates (i.e., 2 slices of toast with cheese, 150 mL of milk with cornflakes, and 150 mL of orange juice).
Studies in healthy male volunteers showed significant alterations in the pharmacokinetics of felodipine when felodipine was administered concomitantly with grapefruit juice. Following the administration of a single dose of plain felodipine 5 mg tablets with 200 mL grapefruit juice or 200 mL water AUC and Cmax of felodipine increased about 3-fold as compared to administration with water. When felodipine extended release tablets were administered as Plendil 10 mg with 250 mL grapefruit juice felodipine AUC and Cmax values doubled as compared to those observed with water. When grapefruit juice was taken for up to 24 hours prior to felodipine administration, a significant pharmacokinetic interaction was observed (see Precautions, Interaction with Grapefruit Juice).
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 years) was only 45% of that in young volunteers (mean age 26 years). At steady state mean AUC for young patients was 39% of that for the elderly patients.
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 hemodynamically inactive.
Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta.
The acute hemodynamic effect of felodipine is a reduction in total peripheral resistance which leads to a decrease in blood pressure associated with a modest reflex increase in heart rate. This reflex increase in heart rate frequently occurs during the first week of therapy and generally attenuates over time. Heart rate increases of 5 to 10 beats/minute may be seen during chronic administration. The effect on the heart rate is inhibited by beta-blocking agents.
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 approximately 24 hours; reductions in diastolic blood pressure at trough plasma levels were 40 to 60% of those at peak plasma levels. The antihypertensive effect is dose-dependent and correlates with the plasma concentration of felodipine.
Felodipine in therapeutic doses has no effect on conduction in the conducting system of the heart and no effect on the AV nodal refractoriness. No direct additional effects to those registered after beta-blockade are observed when felodipine is given concomitantly.
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 have been observed during short- and long-term therapy. No general salt and water retention occurs during long-term therapy. In clinical trials increases in norepinephrine plasma levels have been observed.
Indications
In the treatment of mild to moderate essential hypertension. Felodipine should normally be used in those patients in whom treatment with a diuretic or a beta-blocker was found ineffective or has been associated with unacceptable adverse effects.
Felodipine can be tried as an initial agent in those patients in whom the use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.
Combination of felodipine with a thiazide diuretic or a beta-blocker has been found to be compatible and showed an additive antihypertensive effect. Safety and efficacy of concurrent use of felodipine with other antihypertensive agents has not been established.
Precautions
As with all drugs, care should be exercised when treating patients with multiple medications. Dihydropyridine calcium channel blockers undergo biotransformation by the cytochrome P450 system, mainly via the CYP 3A4 isoenzyme. Coadministration of felodipine with other drugs which follow the same route of biotransformation may result in altered bioavailability of felodipine or these drugs. Dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered felodipine to maintain optimum therapeutic blood levels.
Drugs known to be inhibitors of the cytochrome P450 system include: azole antifungals, cimetidine, cyclosporine, erythromycin, quinidine, warfarin.
Drugs known to be inducers of the cytochrome P450 system include: phenobarbital, phenytoin, rifampin.
Felodipine may increase the concentration of tacrolimus. When used together, the tacrolimus serum concentration should be followed and the tacrolimus dose may need to be adjusted.
Drugs known to be biotransformed via P450 include: benzodiazepines, flecainide, imipramine, propafenone, terfenadine, theophylline.
Cytochrome P450 Enzyme Inhibitors: Cimetidine: In healthy volunteers pharmacokinetic studies showed an approximately 50% increase in the area under the plasma concentration time curve (AUC) as well as the Cmax of felodipine when given concomitantly with cimetidine. It is anticipated that a clinically significant interaction may occur in some hypertensive patients. Therefore, it is recommended that low doses of felodipine be used when given concomitantly with cimetidine.
Erythromycin: Concomitant treatment with erythromycin has been shown to cause an increase in felodipine plasma levels.
Cytochrome P450 Enzyme Inducers: Phenytoin, Carbamazepine and Phenobarbital: In a pharmacokinetic study maximum plasma concentrations of felodipine were considerably lower in epileptic patients on long-term anticonvulsant therapy (phenytoin, carbamazepine, phenobarbital) than in healthy volunteers. The mean area under the felodipine plasma concentration-time curve was also reduced in epileptic patients 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.
Alcohol: Alcohol can enhance the hemodynamic effects of felodipine.
Beta-adrenoceptor 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 36%, 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 as conventional tablets the peak plasma concentration of digoxin was significantly increased. With the extended release formulation of felodipine there was no significant change in peak plasma levels or AUC of digoxin.
Other Concomitant Therapy: In healthy subjects there were no clinically significant interactions when felodipine was given concomitantly with indomethacin or spironolactone.
Patients over 65 years of age may have elevated plasma concentrations of felodipine and, therefore, may require lower doses of felodipine (see Pharmacology, Pharmacokinetics). These patients should have their blood pressure monitored closely during initial administration and after dosage adjustment of felodipine. A dosage of 10 mg daily should not be exceeded (see Dosage, Geriatrics).
Patients with Impaired Liver Function: Patients with impaired liver function may have elevated plasma concentrations of felodipine and, therefore, may require lower doses of felodipine (see Pharmacology, Pharmacokinetics). These patients should have their blood pressure monitored closely during initial administration and after dosage adjustment of felodipine. A dosage of 10 mg daily should not be exceeded (see Dosage, Patients with Impaired Liver Function).
Gingival Hyperplasia: Felodipine can induce gingival enlargement in patients with pronounced gingivitis and parodontitis. However, such changes may be reversed by measures of good oral hygiene and mechanical debridement of the teeth. In very rare instances, felodipine has also caused gingivitis.
Published data show that through inhibition of cytochrome P450, grapefruit juice can increase plasma levels and augment pharmacodynamic effects of dihydropyridine calcium channel blockers. In view of the absolute bioavailability of felodipine, the potential for a significant increase in pharmacodynamic effects exists (see Pharmacology, Pharmacokinetics). Therefore, the consumption of grapefruit juice, prior to or during treatment with felodipine should be avoided.
Felodipine is not recommended in children since the safety and efficacy in children have not been established.
Supplied
Each pink, circular, biconvex, film-coated, extended release tablet, engraved 
on one side and 5 on the other, contains: felodipine 5 mg. Nonmedicinal ingredients: Tablet Core: aluminum silicate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose anhydrous, microcrystalline cellulose, polyoxy 40 hydrogenated castor oil, propyl gallate and sodium stearyl fumarate; Coating Layer: carnauba wax, color iron oxide red-brown, color iron oxide yellow, color titanium dioxide, hydrogen peroxide, hydroxypropyl methylcellulose and polyethylene glycol. Compliance blister packages of 30 tablets.
Each yellow, circular, biconvex, film-coated, extended release tablet, engraved 
on one side and 2.5 on the other, contains: felodipine 2.5 mg. Nonmedicinal ingredients: Tablet Core: aluminum silicate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose anhydrous, microcrystalline cellulose, polyoxy 40 hydrogenated castor oil, propyl gallate and sodium stearyl fumarate; Coating Layer: carnauba wax, color iron oxide yellow, color titanium dioxide, hydrogen peroxide, hydroxypropyl methylcellulose and polyethylene glycol. Compliance blister packages of 30 tablets.
Each red-brown, circular, biconvex, film-coated, extended release tablet, engraved 
on one side and 10 on the other, contains: felodipine 10 mg. Nonmedicinal ingredients: Tablet Core: aluminum silicate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose anhydrous, microcrystalline cellulose, polyoxy 40 hydrogenated castor oil, propyl gallate and sodium stearyl fumarate; Coating Layer: carnauba wax, color iron oxide red-brown, color iron oxide yellow, color titanium dioxide, hydrogen peroxide, hydroxypropyl methylcellulose and polyethylene glycol. Compliance blister packages of 30 tablets.
Note: These extended release tablets must not be divided, crushed or chewed.
Store between 15 and 30°C.
Contraindications
In women of childbearing potential, in pregnancy, and during lactation. Fetal malformations and adverse effects on pregnancy have been reported in animals.
Teratogenic Effects: Studies in pregnant rabbits administered doses of 0.46, 1.2, 2.3 and 4.6 mg/kg/day (from 0.4 to 4 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. 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: In a study on fertility and general reproductive performance in rats, prolongation of parturition with difficult labor and an increased frequency of fetal and early postnatal deaths were observed in the groups treated with doses of 9.6 mg/kg/day 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. This effect occurred only in pregnant rabbits and regressed during lactation. Similar changes in the mammary glands were not observed in rats or monkeys.
Warnings
Congestive Heart Failure: The safety and efficacy of felodipine in patients with heart failure have not been established. Caution should, therefore, be exercised when using felodipine in hypertensive patients with compromised ventricular function, particularly in combination with a beta-blocker. Acute hemodynamic studies in a small number of patients with New York Heart Association Class II or III heart failure treated with felodipine have not demonstrated negative inotropic effects.
Hypotension, Myocardial Ischemia: Felodipine may, occasionally, precipitate symptomatic hypotension and rarely syncope. It may lead to reflex tachycardia which, particularly in patients with severe obstructive coronary artery disease, may result in myocardial ischemia. Careful monitoring of blood pressure during the initial administration and titration of felodipine is recommended.
Care should be taken to avoid hypotension especially in patients with a history of cerebrovascular insufficiency, and in those taking medications known to lower blood pressure.
Beta-blocker Withdrawal: Felodipine gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be a gradual reduction of the dose of beta-blockers.
Outflow Obstruction: Felodipine should be used with caution in the presence of fixed left ventricular outflow obstruction.
Dermatologic Lesions: Along with leucocytoclastic vasculitis, other dermatologic events have been observed. These include rash and flush. All cases of dermatologic lesions should be carefully diagnosed and monitored.
Adverse Effects
abdominal pain, diarrhea, vomiting, dry mouth, flatulence, acid regurgitation, cholestatic hepatitis, gingival hyperplasia, salivary gland enlargement.
arthralgia, muscle cramps, myalgia.
insomnia, depression, anxiety disorders, irritability, nervousness, somnolence, decrease in libido, tremor, confusion.
impotence/sexual dysfunction, urinary frequency, urinary urgency, dysuria, polyuria.
Serious adverse events reported from controlled clinical trials and during marketing experience (incidence <0.5%) were myocardial infarction, hypotension, syncope, angina pectoris, arrhythmia and anemia.
Isolated cases of angioedema have been reported. Angioedema may be accompanied by breathing difficulty.
For the following laboratory values statistically significant decreases were observed; bilirubin, red blood count, hemoglobin, and urate. Statistically significant increases were found in erythrocyte sedimentation rate and thrombocyte count. In isolated cases, there were increased liver enzymes. None of the changes were considered to be of clinical significance.
chest pain, facial edema, flu-like illness, fever.
pruritus, erythema multiforme, erythema nodosum, leucocytoclastic vasculitis, urticaria, photosensitivity reactions.
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 to 10 mg once a day or during postmarketing experience are listed below. These events are listed in order of decreasing severity within each category regardless of relationship to felodipine therapy:
tachycardia, premature beats, postural hypotension, bradycardia.
Overdose
Overdosage can cause excessive peripheral vasodilation with marked hypotension and possibly bradycardia.
In the case of known overdosage, activated charcoal may be used. If severe hypotension occurs, symptomatic treatment should be instituted. The patient should be placed supine with the legs elevated. The i.v. administration of fluids may be used to treat hypotension. Plasma volume may be increased by infusion of a plasma volume expander. When accompanied by bradycardia, atropine 0.5 to 1 mg should be administered i.v. Sympathomimetic drugs predominantly affecting the α1-adrenoceptor may be given if the above-mentioned measures are considered insufficient. Removal of felodipine from the circulation by hemodialysis has not been established.
Dosage
Patients over 65 years of age may develop elevated plasma concentrations of felodipine. A starting dose no higher than 2.5 mg once daily is recommended. A dosage of 10 mg daily should not be exceeded (see Precautions, Geriatrics).
Patients with impaired liver function may develop elevated plasma concentrations of felodipine. A starting dose no higher than 2.5 mg once daily is recommended. A dosage of 10 mg daily should not be exceeded (see Precautions, Patients with Impaired Liver Function).
