Renedil Product Monograph

ACTION AND CLINICAL PHARMACOLOGY

RENEDIL (felodipine) is a calcium ion influx inhibitor (calcium channel blocker).

Felodipine is a member of the dihydropyridine class of calcium channel blockers.

Mechanism of Action

The therapeutic effect of this group of drugs is believed to be related to their specific cellular action of selectively inhibiting transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle. The contractile processes of these tissues are dependent upon the movement of extracellular calcium into the cells through specific ion channels. Felodipine blocks transmembrane influx of calcium through the slow channel without affecting to any significant degree the transmembrane influx of sodium through the fast channel. This results in a reduction of free calcium ions available within cells of the above tissues. Felodipine does not alter total serum calcium. In vitro studies show that the effects of felodipine on contractile mechanisms are selective, with greater effects on vascular smooth muscle than on 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 in man is principally a consequence of a dose-related decrease in peripheral vascular resistance, with a modest reflex increase in heart rate (see ACTION AND CLINICAL PHARMACOLOGY - Pharmacodynamics).

Pharmacokinetics

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 5-20 mg per day. The plasma protein binding of felodipine is approximately 99%. It is bound predominately to the albumin fraction.

Felodipine is extensively metabolized in the liver, predominantly by cytochrome P-450 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 (t_max), and a reduced maximum plasma concentration (C_max). The mean t_max ranges from 2.5 to 5 hours. The area under the plasma concentration versus time curve and C_max are linearly related to the dose in the 10 to 40 mg range. Following administration of RENEDIL to hypertensive patients, mean C_max 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 C_max and AUC after repeated dosing is approximately threefold and indicates a need for individualized dosing. The bioavailability of RENEDIL is not influenced by the presence of food in the gastrointestinal tract. However, the peak plasma concentration of felodipine (C_max) is significantly increased by 1.5 to 2 fold when RENEDIL 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 C_max may cause a clinically significant fall in blood pressure. Therefore, RENEDIL should not be administered with meals rich in carbohydrate or fat. However, the absorption characteristics of felodipine are not affected when RENEDIL is administered with a light meal low in fat and carbohydrates (i.e. 2 slices of toast with cheese, 150 mL milk with cornflakes, and 150 mL orange juice) (See DOSAGE AND ADMINISTRATION).

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 C_max of felodipine increased about threefold as compared to administration with water. When felodipine extended release tablets were administered as RENEDIL 10 mg with 250 mL grapefruit juice, felodipine AUC and C_max values doubled as compared to those observed with water. When grapefruit juice was taken for up to 24 hours prior to RENEDIL 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 percent of that in young volunteers (mean age 26 years). At steady state mean AUC for young patients was 39 percent of that for the elderly patients.

In patients with hepatic disease, the clearance of felodipine was reduced to about 60 percent 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. Pharmacodynamics

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 5-10 beats per minute may be seen during chronic administration. The effect on the heart rate is inhibited by beta-blocking agents.

Following administration of RENEDIL a reduction in blood pressure generally occurs within two to five hours.

During chronic administration, substantial blood pressure control lasts for approximately 24 hours; reductions in diastolic blood pressure at trough plasma levels were 40-60 percent 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 A-V nodal refractoriness. No direct additional effects to those registered after beta-blockade are observed when RENEDIL 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 noradrenaline plasma levels have been observed.

INDICATIONS AND CLINICAL USE

RENEDIL (felodipine) is indicated in the treatment of mild to moderate essential hypertension. RENEDIL 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.

RENEDIL 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 RENEDIL 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 RENEDIL with other antihypertensive agents has not been established.

CONTRAINDICATIONS

RENEDIL (felodipine) is contraindicated in:

1. 1. Patients with a known hypersensitivity to felodipine or other components of RENEDIL.
2. 2. Patients with a known hypersensitivity to other dihydropyridines.
3. 3. 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 percent of the fetuses.

Non-Teratogenic Effects

In a study on fertility and general reproductive performance in rats, prolongation of parturition with difficult labour 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 RENEDIL (felodipine) in patients with heart failure has not been established. Caution should, therefore, be exercised when using RENEDIL 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

RENEDIL 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

RENEDIL 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

RENEDIL 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.

PRECAUTIONS

Peripheral Edema

Mild to moderate peripheral edema was the most common adverse event in the clinical trials. The incidence of peripheral edema was dose-dependent. Frequency of peripheral edema ranged from about 10 percent in patients under 50 years of age taking 5 mg daily to about 30 percent in those over 60 years of age taking 20 mg daily. This adverse effect generally occurs within 2-3 weeks of the initiation of treatment. Care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction.

Use in Elderly Patients

Patients over 65 years of age may have elevated plasma concentrations of felodipine and, therefore, may require lower doses of RENEDIL (see ACTION AND CLINICAL PHARMACOLOGY - Pharmacokinetics). These patients should have their blood pressure monitored closely during initial administration and after dosage adjustment of RENEDIL. A dosage of 10 mg daily should not be exceeded (see DOSAGE AND ADMINISTRATION - Use in the Elderly).

Use in Patients with Impaired Liver Function

Patients with impaired liver function may have elevated plasma concentrations of felodipine and, therefore, may require lower doses of RENEDIL (see ACTION AND CLINICAL PHARMACOLOGY -Pharmacokinetics). These patients should have their blood pressure monitored closely during initial administration and after dosage adjustment of RENEDIL. A dosage of 10 mg daily should not be exceeded (see DOSAGE AND ADMINISTRATION - Use in Patients with Impaired Liver Function).

Gingival Hyperplasia

RENEDIL 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, RENEDIL has also caused gingivitis.

Pregnancy and Lactation

See CONTRAINDICATIONS.

Use in Children

RENEDIL is not recommended in children since the safety and efficacy in children have not been established.

Interaction with Grapefruit Juice

Published data show that through inhibition of cytochrome P-450, grapefruit juice can increase plasma levels and augment pharmacodynamic effects of dihydropyridine calcium channel blockers. In view of the absolute bioavailability of RENEDIL, the potential for a significant increase in pharmacodynamic effects exists (see ACTION AND CLINICAL PHARMACOLOGY- Pharmacokinetics). Therefore, consumption of grapefruit juice prior to or during treatment with RENEDIL should be avoided.

Drug Interactions

As with all drugs, care should be exercised when treating patients with multiple medications. Dihydropyridine calcium channel blockers undergo biotransformation by the cytochrome P-450 system, mainly via the CYP 3A4 isoenzyme. Coadminisration 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 P-450 system include: azole antifungals, cimetidine, cyclosporine, erythromycin, quinidine, warfarin.

Drugs known to be inducers of the cytochrome P-450 system include: phenobarbital, phenytoin, rifampin.

Drugs known to be biotransformed via P-450 include: benzodiazepines, flecainide, imipramine, propafenone, terfenadine, theophylline.

Felodipine may also increase the concentration of tacrolimus. When used together, the tacrolimus serum concentration should be followed and the tacrolimus dose may need to be adjusted.

Cytochome P-450 Enzyme Inhibitors

Cimetidine

In healthy volunteers pharmacokinetic studies showed an approximately 50 percent increase in the area under the plasma concentration time curve (AUC) as well as the C_max 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 RENEDIL be used when given concomitantly with cimetidine.

Erythromycin

Concomitant treatment with erythromycin has been shown to cause an increase in felodipine plasma levels.

Cytochrome P-450 Enzyme Inducers

Phenytoin, Carbamazepine and Phenobarbital

In a phamacokinetic 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 may 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 C_max of metoprolol, however, were increased approximately 31 and 36 percent, 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.

ADVERSE REACTIONS

In 861 patients with essential hypertension treated once daily with 2.5 to 10 mg RENEDIL (felodipine) as monotherapy in controlled clinical trials, the most common clinical adverse events were peripheral edema and headache.

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, without regard to causality, are listed by dose in Table 1 below. These events are reported from controlled clinical trials with patients who were randomized to either a fixed dose of RENEDIL 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 RENEDIL 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).

Table 1. Percent of patients with adverse events in controlled trials of RENEDIL (N=861)* as monotherapy without regard to causality (incidence of discontinuations shown in parentheses).

* Some patients have been exposed to more than one dose level of RENEDIL.

Adverse events that occurred in 0.5 up to 1.5 percent of patients who received RENEDIL in all controlled clinical trials at the recommended dosage range of 2.5 to 10 mg once a day are listed below. These events are listed in order to decreasing severity within each category regardless of relationship to RENEDIL therapy: Body as a Whole: Chest pain, facial edema, flu-like illness, fever; Cardiovascular: Tachycardia, premature beats, postural hypotension, bradycardia; Gastrointestinal: Abdominal pain, diarrhea, vomiting, dry mouth, flatulence, acid regurgitation, cholestatic hepatitis, gingival hyperplasia, salivary gland enlargement; Metabolic: ALT (SGPT) increased; Musculoskeletal: Arthralgia, muscle cramps, myalgia; Nervous/Psychiatric: Insomnia, depression, anxiety disorders, irritability, nervousness, somnolence, decrease in libido, tremor, confusion; Respiratory: Dyspnea, epistaxis; Dermatologic: Pruritis, erythema multiforme, erythema nodosum, leucocytoclastic vasculitis, urticaria, photosensitivity reactions; Special Senses: Visual disturbances; Urogenital: Impotence/sexual dysfunction, urinary frequency, urinary urgency, dysuria, polyuria.

Serious adverse events reported from controlled clinical trials and during marketing experience (incidence <0.5 percent) were myocardial infarction, hypotension, syncope, angina pectoris, arrhythmia and anemia.

Isolated cases of angioedema have been reported. Angioedema may be accompanied by breathing difficulty.

Laboratory Tests

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.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Symptoms

Overdosage can cause excessive peripheral vasodilation with marked hypotension and possibly bradycardia.

Treatment

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 intravenous 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 0.5-1 mg should be administered intravenously. Sympathomimetic drugs predominantly affecting the "₁-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 AND ADMINISTRATION

RENEDIL should be swallowed whole and not crushed or chewed. The tablets should not be administered with a meal rich in carbohydrates or fat (see ACTION AND CLINICAL PHARMACOLOGY -Pharmacokinetics).

The usual recommended initial dose is 5 mg once daily (see DOSAGE AND ADMINISTRATION - Use in the Elderly, and - Use in Patients with Impaired Liver Function).

Depending on the patient’s response, the dosage should be adjusted accordingly. Dose adjustment, if necessary, should be done at intervals of not less than two weeks.

The maintenance dosage range is 2.5 to 10 mg once daily.

In clinical trials, doses above 10 mg daily showed an increased blood pressure response but a disproportionately higher incidence of peripheral edema and other vasodilatory adverse events.

Modification of the recommended dosage is usually not required in patients with renal impairment.

Use in the Elderly

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 - Use in Elderly Patients).

Use in Patients with Impaired Liver Function

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 - Use in Patients with Impaired Liver Function).

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: felodipine

Chemical Name: 3,5-pyridinedicarboxylic acid,4-(2,3-dichlorophenyl)-1,4-

dihydro-2,6-dimethyl-, ethyl methyl ester

Structural Formula:

Molecular Formula: C₁₈H₁₉Cl₂NO₄

Molecular Weight: 384.26

Description: Felodipine is a slightly yellowish, crystalline powder. It is not hygroscopic. It is soluble in acetone, dichloromethane, ethanol, heptane, methanol, n-octanol, 2-propanol, and practically insoluble in water.

Composition

2.5 mg 5 mg 10 mg

Tablet Core mg/tab felodipine

hydroxypropyl methylcellulose

lactose anhydrous

polyoxyl 40 hydrogenated castor oil

hydroxypropyl cellulose

propyl gallate

aluminum silicate

microcrystalline cellulose

sodium stearyl fumarate

2.5

Coating Layer

hydroxypropyl methylcellulose

polyethylene glycol

titanium dioxide

iron oxide yellow

iron oxide red-brown

carnauba wax

Stability and Storage Recommendations

Store RENEDIL at 15-30^oC.

AVAILABILITY OF DOSAGE FORMS

RENEDIL tablets are extended release, film-coated tablets, containing felodipine in strengths of 2.5 mg, 5 mg and 10 mg.

RENEDIL 2.5 mg Tablet: A yellow, circular, biconvex film-coated tablet, engraved H

FF on one side and 2.5 on the other.

RENEDIL 5 mg Tablet: A pink, circular, biconvex film-coated tablet, engraved H

FC on one side and 5 on the other.

RENEDIL 10 mg Tablet: A red-brown, circular, biconvex film-coated tablet, engraved H

FD on one side and 10 on the other

Each tablet strength is available in compliance packages (2 x 15).

NOTE: These extended release tablets must not be divided, crushed or chewed.