Felodipine Tablets Usp

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 nonfatal 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 one 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 (e.g., 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.

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 mg to 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 extended-release tablets should regularly be taken either without

food or with a light meal (see CLINICAL PHARMACOLOGY, Pharmacokinetics

and Metabolism). Felodipine extended-release tablets should be swallowed

whole and not crushed or chewed.

Felodipine extended-release tablets are contraindicated in patients who are

hypersensitive to this product.

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 extendedrelease

tablets 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 extended-release tablets,

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 extendedrelease

tablets, 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 extended-release tablets 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 extended-release tablets 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

felodipine extended-release tablets 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

extended-release tablets 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. (See PRECAUTIONS: Information for Patients.)

Clinical Laboratory Test Findings

Serum Electrolytes

No significant effects on serum electrolytes were observed during short- and

long-term therapy (see CLINICAL PHARMACOLOGY: Renal/Endocrine

Effects).

Serum Glucose

No significant effects on fasting serum glucose were observed in patients

treated with felodipine extended-release tablets in the U.S. controlled study.

Liver Enzymes

One of two episodes of elevated serum transaminases decreased once drug

was discontinued in clinical studies; no follow-up was available for the other

patient.

CYP3A4 Inhibitors

Felodipine is metabolized by CYP3A4. Coadministration of CYP3A4 inhibitors

(e.g., 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 coadministration of itraconazole (a potent CYP3A4 inhibitor).

Caution should be used when CYP3A4 inhibitors are coadministered with

felodipine. A conservative approach to dosing felodipine should be taken. The

following specific interactions have been reported:

Itraconazole

Coadministration 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 Cmax, and 2-fold prolongation in the half-life of

felodipine.

Erythromycin

Coadministration of felodipine extended-release tablets with erythromycin

resulted in approximately 2.5-fold increase in the AUC and Cmax, and about

2-fold prolongation in the half-life of felodipine.

Grapefruit Juice

Coadministration of felodipine extended-release tablets 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

Coadministration 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 extended-release tablets the

pharmacokinetics of digoxin in patients with heart failure were 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 interactions when

felodipine was given concomitantly with indomethacin or spironolactone.

Interaction with Food

See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.

Felodipine Extended-release Tablets, USP are available containing 2.5 mg,

5 mg or 10 mg of felodipine, USP.

The 2.5 mg tablets are white film-coated, round, unscored tablets debossed

with “YSP 211 ”on one side of the tablets. They are available as follows:



NDC 71205-920-30 bottles of 30 tablets

NDC 71205-920-60 bottles of 60 tablets

NDC 71205-920-90 bottles of 90 tablets

NDC 71205-920-00 bottles of 100 tablets

NDC 71205-920-72 bottles of 120 tablets

NDC 71205-920-55 bottles of 500 tablets

The 5 mg tablets are orange film-coated, round, unscored tablets debossed

with “YSP 210” on one side of the tablets. They are available as follows:

NDC 71205-921-30 bottles of 30 tablets

NDC 71205-921-60 bottles of 60 tablets

NDC 71205-921-90 bottles of 90 tablets

NDC 71205-921-00 bottles of 100 tablets

NDC 71205-921-72 bottles of 120 tablets

NDC 71205-921-55 bottles of 500 tablets

The 10 mg tablets are red film-coated, round, unscored tablets debossed with

“YSP 051” on one side of the tablets. They are available as follows:

NDC 71205-922-30 bottles of 30 tablets

NDC 71205-922-60 bottles of 60 tablets

NDC 71205-922-90 bottles of 90 tablets

NDC 71205-922-00 bottles of 100 tablets

NDC 71205-922-72 bottles of 120 tablets

NDC 71205-922-55 bottles of 500 tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a

child-resistant closure.

Manufactured by:

Yung Shin Pharmaceutical Ind. Co., Ltd.

Tachia, Taichung 43769, TAIWAN

Distributed by:

Carlsbad Technology, Inc.

5922 Farnsworth Court, Carlsbad, CA 92008, USA

Repackaged and Relabeled by:

Proficient Rx LP

Thousand Oaks, CA 91320

Revised: 03/2019

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 C18H19Cl12NO4 and its structural formula is:

Felodipine, USP is a light yellow to yellow crystalline powder with a molecular

weight of 384.26. It is insoluble in water and is freely soluble in acetone and

in methanol; very slightly soluble in heptane. 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,

USP for oral administration. Inactive ingredients are: lactose monohydrate,

hydroxypropyl cellulose, silicon dioxide colloidal, hypromellose, magnesium

stearate, calcium phosphate dibasic, butylated hydroxyanisole, polyethylene

glycol, titanuium dioxide. In addition, the 5 mg and the 10 mg tablet strength

contain FD&C Red No. 40 powder, FD&C Yellow No. 6 Aluminum Lake.

Meets USP Dissolution Test 3.

Hypotension

Felodipine, like other calcium antagonists, may occasionally precipitate

significant hypotension and, rarely, syncope. It may lead to reflex tachycardia

which in susceptible individuals may precipitate angina pectoris. (See

ADVERSE REACTIONS.)

Heart Failure

Although acute hemodynamic studies in a small number of patients with

NYHA Class II or III heart failure treated with felodipine have not demonstrated

negative inotropic effects, safety in patients with heart failure has not

been established. Caution, therefore, should be exercised when using

ffelodipine extended-release tablets in patients with heart failure or compromised

ventricular function, particularly in combination with a beta-blocker.

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, a starting dose of 2.5 mg once a day is recommended.

These patients should have their blood pressure monitored closely during

dosage adjustment of felodipine extended-release tablets. (See CLINICAL

PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)

Peripheral Edema

Peripheral edema, generally mild and not associated with generalized fluid

retention, was the most common adverse event in the clinical trials. The

incidence of peripheral edema was both dose and age dependent. Frequency

of peripheral edema ranged from about 10% in patients under 50 years of

age taking 5 mg daily to about 30% in those over 60 years of age taking 20

mg daily. This adverse effect generally occurs within 2 to 3 weeks of the

initiation of treatment.

Teratogenic Effects. Pregnancy Category C

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/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 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.

**Based on patient weight of 50 kg

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/m2 basis).

This effect occurred only in pregnant rabbits and regressed during lactation.

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 extended-release tablet 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.

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 mg to 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 poisoncontrol

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.

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.

Safety and effectiveness in pediatric patients have not been established.

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.

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 mg to 20 mg. In those studies felodipine was administered

either as monotherapy or was added to beta-blockers. The results of the two

studies with felodipine extended-release tablets given once daily as monotherapy

are shown in the table below:

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.

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.

Following administration of felodipine extended-release tablets, 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% to 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 to

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.

Patients should be instructed to take felodipine extended-release tablets

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 felodipine extended-release tablets 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.

Following oral administration, felodipine is almost completely absorbed and

undergoes extensive first-pass metabolism. The systemic bioavailability of

felodipine extended-release tablets is approximately 20%. Mean peak

concentrations following the administration of felodipine extended-release

tablets 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 t1/2.

Following oral administration of the immediate-release formulation, the plasma

level of felodipine also declined polyexponentially with a mean terminal t1/2 of

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 (EC50)

[4 to 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 extended-release tablets were 23 and 7 nmol/L. Since the

EC50 for felodipine is 4 to 6 nmol/L, a 5 mg to 10 mg dose of felodipine

extended-release tablets 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 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 14C-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 extended-release tablets 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 extended-release tablets is influenced by the

presence of food. When administered either with a high fat or carbohydrate

diet, Cmax is increased by approximately 60%; AUC is unchanged. When

felodipine extended-release tablets were 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

2-fold when taken with grapefruit juice. Orange juice does not appear

to modify the kinetics of felodipine extended-release tablets. A similar finding

has been seen with other dihydropyridine calcium antagonists, but to a lesser

extent than that seen with felodipine.

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 (see CLINICAL

PHARMACOLOGY).

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/m2 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/m2 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/m2 basis) for

periods of up to 80 weeks in males and 99 weeks in females.

Felodipine did not display any mutagenic activity in vitro in the Ames

microbial mutagenicity test or in the mouse lymphoma forward mutation

assay. No clastogenic potential was seen in vivo in the mouse micronucleus

test at oral doses up to 2500 mg/kg (1,100 times** the maximum recommended

human dose on a mg/m2 basis) or in vitro 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/m2 basis) showed no significant effect of felodipine on

reproductive performance.

**Based on patient weight of 50 kg

Hypotension

Felodipine, like other calcium antagonists, may occasionally precipitate

significant hypotension and, rarely, syncope. It may lead to reflex tachycardia

which in susceptible individuals may precipitate angina pectoris. (See

ADVERSE REACTIONS.)

Heart Failure

Although acute hemodynamic studies in a small number of patients with

NYHA Class II or III heart failure treated with felodipine have not demonstrated

negative inotropic effects, safety in patients with heart failure has not

been established. Caution, therefore, should be exercised when using

ffelodipine extended-release tablets in patients with heart failure or compromised

ventricular function, particularly in combination with a beta-blocker.

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, a starting dose of 2.5 mg once a day is recommended.

These patients should have their blood pressure monitored closely during

dosage adjustment of felodipine extended-release tablets. (See CLINICAL

PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)

Peripheral Edema

Peripheral edema, generally mild and not associated with generalized fluid

retention, was the most common adverse event in the clinical trials. The

incidence of peripheral edema was both dose and age dependent. Frequency

of peripheral edema ranged from about 10% in patients under 50 years of

age taking 5 mg daily to about 30% in those over 60 years of age taking 20

mg daily. This adverse effect generally occurs within 2 to 3 weeks of the

initiation of treatment.

Teratogenic Effects. Pregnancy Category C

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/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 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.

**Based on patient weight of 50 kg

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/m2 basis).

This effect occurred only in pregnant rabbits and regressed during lactation.

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 extended-release tablet 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.

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 mg to 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 poisoncontrol

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.

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 C18H19Cl12NO4 and its structural formula is:

Felodipine, USP is a light yellow to yellow crystalline powder with a molecular

weight of 384.26. It is insoluble in water and is freely soluble in acetone and

in methanol; very slightly soluble in heptane. 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,

USP for oral administration. Inactive ingredients are: lactose monohydrate,

hydroxypropyl cellulose, silicon dioxide colloidal, hypromellose, magnesium

stearate, calcium phosphate dibasic, butylated hydroxyanisole, polyethylene

glycol, titanuium dioxide. In addition, the 5 mg and the 10 mg tablet strength

contain FD&C Red No. 40 powder, FD&C Yellow No. 6 Aluminum Lake.

Meets USP Dissolution Test 3.

Felodipine Extended-release Tablets, USP are available containing 2.5 mg,

5 mg or 10 mg of felodipine, USP.

The 2.5 mg tablets are white film-coated, round, unscored tablets debossed

with “YSP 211 ”on one side of the tablets. They are available as follows:



NDC 71205-920-30 bottles of 30 tablets

NDC 71205-920-60 bottles of 60 tablets

NDC 71205-920-90 bottles of 90 tablets

NDC 71205-920-00 bottles of 100 tablets

NDC 71205-920-72 bottles of 120 tablets

NDC 71205-920-55 bottles of 500 tablets

The 5 mg tablets are orange film-coated, round, unscored tablets debossed

with “YSP 210” on one side of the tablets. They are available as follows:

NDC 71205-921-30 bottles of 30 tablets

NDC 71205-921-60 bottles of 60 tablets

NDC 71205-921-90 bottles of 90 tablets

NDC 71205-921-00 bottles of 100 tablets

NDC 71205-921-72 bottles of 120 tablets

NDC 71205-921-55 bottles of 500 tablets

The 10 mg tablets are red film-coated, round, unscored tablets debossed with

“YSP 051” on one side of the tablets. They are available as follows:

NDC 71205-922-30 bottles of 30 tablets

NDC 71205-922-60 bottles of 60 tablets

NDC 71205-922-90 bottles of 90 tablets

NDC 71205-922-00 bottles of 100 tablets

NDC 71205-922-72 bottles of 120 tablets

NDC 71205-922-55 bottles of 500 tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a

child-resistant closure.

Manufactured by:

Yung Shin Pharmaceutical Ind. Co., Ltd.

Tachia, Taichung 43769, TAIWAN

Distributed by:

Carlsbad Technology, Inc.

5922 Farnsworth Court, Carlsbad, CA 92008, USA

Repackaged and Relabeled by:

Proficient Rx LP

Thousand Oaks, CA 91320

Revised: 03/2019

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.

Safety and effectiveness in pediatric patients have not been established.

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.

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 mg to 20 mg. In those studies felodipine was administered

either as monotherapy or was added to beta-blockers. The results of the two

studies with felodipine extended-release tablets given once daily as monotherapy

are shown in the table below:

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 extendedrelease

tablets 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 extended-release tablets,

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 extendedrelease

tablets, 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 extended-release tablets 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 extended-release tablets 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

felodipine extended-release tablets 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

extended-release tablets 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. (See PRECAUTIONS: Information for Patients.)

Clinical Laboratory Test Findings

Serum Electrolytes

No significant effects on serum electrolytes were observed during short- and

long-term therapy (see CLINICAL PHARMACOLOGY: Renal/Endocrine

Effects).

Serum Glucose

No significant effects on fasting serum glucose were observed in patients

treated with felodipine extended-release tablets in the U.S. controlled study.

Liver Enzymes

One of two episodes of elevated serum transaminases decreased once drug

was discontinued in clinical studies; no follow-up was available for the other

patient.

Felodipine extended-release tablets are contraindicated in patients who are

hypersensitive to this product.

CYP3A4 Inhibitors

Felodipine is metabolized by CYP3A4. Coadministration of CYP3A4 inhibitors

(e.g., 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 coadministration of itraconazole (a potent CYP3A4 inhibitor).

Caution should be used when CYP3A4 inhibitors are coadministered with

felodipine. A conservative approach to dosing felodipine should be taken. The

following specific interactions have been reported:

Itraconazole

Coadministration 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 Cmax, and 2-fold prolongation in the half-life of

felodipine.

Erythromycin

Coadministration of felodipine extended-release tablets with erythromycin

resulted in approximately 2.5-fold increase in the AUC and Cmax, and about

2-fold prolongation in the half-life of felodipine.

Grapefruit Juice

Coadministration of felodipine extended-release tablets 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

Coadministration 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 extended-release tablets the

pharmacokinetics of digoxin in patients with heart failure were 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 interactions when

felodipine was given concomitantly with indomethacin or spironolactone.

Interaction with Food

See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.

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.

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.

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 nonfatal 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 one 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 (e.g., 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.

Following administration of felodipine extended-release tablets, 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% to 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 to

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.

Patients should be instructed to take felodipine extended-release tablets

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 felodipine extended-release tablets 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.

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 mg to 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 extended-release tablets should regularly be taken either without

food or with a light meal (see CLINICAL PHARMACOLOGY, Pharmacokinetics

and Metabolism). Felodipine extended-release tablets should be swallowed

whole and not crushed or chewed.

Following oral administration, felodipine is almost completely absorbed and

undergoes extensive first-pass metabolism. The systemic bioavailability of

felodipine extended-release tablets is approximately 20%. Mean peak

concentrations following the administration of felodipine extended-release

tablets 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 t1/2.

Following oral administration of the immediate-release formulation, the plasma

level of felodipine also declined polyexponentially with a mean terminal t1/2 of

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 (EC50)

[4 to 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 extended-release tablets were 23 and 7 nmol/L. Since the

EC50 for felodipine is 4 to 6 nmol/L, a 5 mg to 10 mg dose of felodipine

extended-release tablets 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 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 14C-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 extended-release tablets 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 extended-release tablets is influenced by the

presence of food. When administered either with a high fat or carbohydrate

diet, Cmax is increased by approximately 60%; AUC is unchanged. When

felodipine extended-release tablets were 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

2-fold when taken with grapefruit juice. Orange juice does not appear

to modify the kinetics of felodipine extended-release tablets. A similar finding

has been seen with other dihydropyridine calcium antagonists, but to a lesser

extent than that seen with felodipine.

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 (see CLINICAL

PHARMACOLOGY).

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/m2 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/m2 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/m2 basis) for

periods of up to 80 weeks in males and 99 weeks in females.

Felodipine did not display any mutagenic activity in vitro in the Ames

microbial mutagenicity test or in the mouse lymphoma forward mutation

assay. No clastogenic potential was seen in vivo in the mouse micronucleus

test at oral doses up to 2500 mg/kg (1,100 times** the maximum recommended

human dose on a mg/m2 basis) or in vitro 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/m2 basis) showed no significant effect of felodipine on

reproductive performance.

**Based on patient weight of 50 kg