FELODIPINE - felodipine tablet, film coated, extended release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
FELODIPINE (UNII: OL961R6O2C) (FELODIPINE - UNII:OL961R6O2C)
Available from:
Bryant Ranch Prepack
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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 non-fatal 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 1 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 pharmacol
Product summary:
Product: 71335-1318 NDC: 71335-1318-1 30 TABLET, FILM COATED, EXTENDED RELEASE in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
71335-1318-1

FELODIPINE - felodipine tablet, film coated, extended release

Bryant Ranch Prepack

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Felodipine Extended-Release Tablets, USP

Rx only

DESCRIPTION

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 C

H Cl

NO 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 dichloromethane and ethanol. Felodipine is a racemic mixture.

Felodipine extended-release tablets, USP provide extended release of felodipine USP. They are

available as tablets containing 2.5 mg, 5 mg or 10 mg of felodipine USP for oral administration. In

addition to the active ingredient felodipine, the tablets contain the following inactive ingredients:

colloidal silicon dioxide, heavy aluminium silicate, hydroxypropyl cellulose, hydroxypropyl methyl

cellulose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, polyoxyl 40

hydrogenated castor oil, propyl gallate, sodium stearyl fumarate, titanium dioxide. In addition the 2.5 mg

strength contains FD&C blue #2/Indigo carmine aluminum lake and iron oxide yellow and the 5 mg and

10 mg strengths contain iron oxide red and iron oxide yellow.

CLINICAL PHARMACOLOGY

Mechanism of Action

Felodipine is a member of the dihydropyridine class of calcium channel antagonists (calcium channel

blockers). It reversibly competes with nitrendipine and/or other calcium channel blockers for

dihydropyridine binding sites, blocks voltage-dependent Ca

currents in vascular smooth muscle and

cultured rabbit atrial cells, and blocks potassium-induced contracture of the rat portal vein.

In vitro studies show that the effects of felodipine on contractile processes are selective, with greater

effects on vascular smooth muscle than cardiac muscle. Negative inotropic effects can be detected in

vitro, but such effects have not been seen in intact animals.

The effect of felodipine on blood pressure is principally a consequence of a dose-related decrease of

peripheral vascular resistance in man, with a modest reflex increase in heart rate (see Cardiovascular

Effects). With the exception of a mild diuretic effect seen in several animal species and man, the effects

of felodipine are accounted for by its effects on peripheral vascular resistance.

Pharmacokinetics and Metabolism

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 t

Following oral administration of the immediate-release formulation, the plasma level of felodipine also

declined polyexponentially with a mean terminal t

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 (EC

) [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 EC

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 below and DOSAGE AND ADMINISTRATION).

The systemic plasma clearance of felodipine in young healthy subjects is about 0.8 L/min, and the

apparent volume of distribution is about 10 L/kg.

Following an oral or intravenous dose of

C-labeled felodipine in man, about 70% of the dose of

radioactivity was recovered in urine and 10% in the feces. A negligible amount of intact felodipine is

recovered in the urine and feces (< 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, C

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

juice, toast, and cereal), however, there is no effect on felodipine’s pharmacokinetics. The

bioavailability of felodipine was increased approximately two-fold when taken with grapefruit juice.

Orange juice does not appear to modify the kinetics of felodipine extended-release tablets. A similar

finding has been seen with other dihydropyridine calcium antagonists, but to a lesser extent than that

seen with felodipine.

Geriatric Use

Plasma concentrations of felodipine, after a single dose and at steady state, increase with age. Mean

clearance of felodipine in elderly hypertensives (mean age 74) was only 45% of that of young

volunteers (mean age 26). At steady state mean AUC for young patients was 39% of that for the elderly.

Data for intermediate age ranges suggest that the AUCs fall between the extremes of the young and the

elderly.

Hepatic Dysfunction

In patients with hepatic disease, the clearance of felodipine was reduced to about 60% of that seen in

normal young volunteers.

Renal impairment does not alter the plasma concentration profile of felodipine; although higher

concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these are

inactive.

Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta.

Cardiovascular Effects

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/Endocrine Effects

Renal vascular resistance is decreased by felodipine while glomerular filtration rate remains

unchanged. Mild diuresis, natriuresis, and kaliuresis have been observed during the first week of

therapy. No significant effects on serum electrolytes were observed during short- and long-term

therapy.

In clinical trials in patients with hypertension, increases in plasma noradrenaline levels have been

observed.

Clinical Studies

Felodipine produces dose-related decreases in systolic and diastolic blood pressure as demonstrated in

six placebo-controlled, dose response studies using either immediate-release or extended-release

dosage forms. These studies enrolled over 800 patients on active treatment, at total daily doses ranging

from 2.5 to 20 mg. In those studies felodipine was administered either as monotherapy or was added to

beta blockers. The results of the 2 studies with felodipine extended-release tablets given once daily as

monotherapy are shown in the table below:

MEAN REDUCTIONS IN BLOOD PRESSURE (mmHg)*

Placebo response subtracted

Different number of patients available for peak and trough measurements

Dose

N

Systolic /

Diastolic Mean

Peak Response

Mean Trough

Response

Trough/Peak

Ratios (%s)

Study 1 (8 weeks)

2.5 mg

9.4/4.7

2.7/2.5

29/53

5 mg

9.5/6.3

2.4/3.7

25/59

10 mg

18/10.8

10/6

56/56

Study 2 (4 weeks)

10 mg

5.3/7.2

1.5/3.2

33/40**

20 mg

11.3/10.2

4.5/3.2

43/34**

INDICATIONS AND USAGE

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 non-fatal 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 1 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.

CONTRAINDICATIONS

Felodipine extended-release tablets are contraindicated in patients who are hypersensitive to this

product.

PRECAUTIONS

General

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 felodipine

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.

Information for Patients

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.

Drug Interactions

CYP3A4 Inhibitors

Felodipine is metabolized by CYP3A4. Co-administration 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 co-administration of

itraconazole (a potent CYP3A4 inhibitor). Caution should be used when CYP3A4 inhibitors are co-

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

following specific interactions have been reported:

Itraconazole

Co-administration 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 C

, and 2-fold

prolongation in the half-life of felodipine.

Erythromycin

Co-administration of felodipine extended-release tablets erythromycin resulted in approximately 2.5-

fold increase in the AUC and C

, and about 2-fold prolongation in the half-life of felodipine.

Grapefruit Juice

Co-administration of felodipine with grapefruit juice resulted in more than 2-fold increase in the AUC

and C

, but no prolongation in the half-life of felodipine.

Cimetidine

Co-administration of felodipine with cimetidine (a non-specific CYP-450 inhibitor) resulted in an

increase of approximately 50% in the AUC and the C

, 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 C

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year carcinogenicity study in rats fed felodipine at doses of 7.7, 23.1 or 69.3 mg/kg/day (up to 61

times

the maximum recommended human dose on a mg/m basis), a dose-related increase in the

incidence of benign interstitial cell tumors of the testes (Leydig cell tumors) was observed in treated

male rats. These tumors were not observed in a similar study in mice at doses up to 138.6 mg/kg/day (61

times

the maximum recommended human dose on a mg/m basis). Felodipine, at the doses employed in

the 2-year rat study, has been shown to lower testicular testosterone and to produce a corresponding

increase in serum luteinizing hormone in rats. The Leydig cell tumor development is possibly

secondary to these hormonal effects which have not been observed in man.

In this same rat study a dose-related increase in the incidence of focal squamous cell hyperplasia

compared to control was observed in the esophageal groove of male and female rats in all dose groups.

No other drug-related esophageal or gastric pathology was observed in the rats or with chronic

administration in mice and dogs. The latter species, like man, has no anatomical structure comparable to

the esophageal groove.

Felodipine was not carcinogenic when fed to mice at doses up to 138.6 mg/kg/day (61 times

maximum recommended human dose on a mg/m basis) for periods of up to 80 weeks in males and 99

weeks in females.

Felodipine did not display any mutagenic activity in 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 (1100 times

the maximum recommended human dose

on a mg/m basis) or in vitro in a human lymphocyte chromosome aberration assay.

on a mg/m 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/m basis) showed no significant

effect of felodipine on reproductive performance.

____________________________

Based on patient weight of 50 kg

Pregnancy

Pregnancy Category C

Teratogenic Effects

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/m 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/m basis) 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 (2.1 times the maximum human dose

on a mg/m 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 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.

___________________________

Based on patient weight of 50 kg

Nursing Mothers

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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of felodipine did not include sufficient numbers of subjects aged 65 and over to

determine whether they respond differently from younger subjects. Other reported clinical experience

has not identified differences in responses between the elderly and younger patients. Pharmacokinetics,

however, indicate that the availability of felodipine is increased in older patients (see CLINICAL

PHARMACOLOGY: Geriatric Use). In general, dose selection for an elderly patient should be

cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of

decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

In controlled studies in the United States and overseas, approximately 3000 patients were treated with

felodipine as either the extended-release or the immediate-release formulation.

The most common clinical adverse events reported with felodipine extended-release

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 extended-release 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).

Percent of Patients with Adverse Events in Controlled Trials* of Felodipine Extended-Release

Tablets (N = 861) as Monotherapy without Regard to Causality (Incidence of discontinuations

shown in parentheses)

Body System

Adverse Events

Placebo

N = 334

2.5 mg

N = 255

5 mg

N = 581

10 mg

N = 408

Body as a Whole

Peripheral Edema

3.3 (0)

2 (0)

8.8 (2.2)

17.4 (2.5)

Asthenia

3.3 (0)

3.9 (0)

3.3 (0)

2.2 (0)

Warm Sensation

0 (0)

0 (0)

0.9 (0.2)

1.5 (0)

Cardiovascular

Palpitation

2.4 (0)

0.4 (0)

1.4 (0.3)

2.5 (0.5)

Digestive

Nausea

1.5 (0.9)

1.2 (0)

1.7 (0.3)

1 (0.7)

Dyspepsia

1.2 (0)

3.9 (0)

0.7 (0)

0.5 (0)

Patients in titration studies may have been exposed to more than one dose level of felodipine extended-

release tablets.

Constipation

0.9 (0)

1.2 (0)

0.3 (0)

1.5 (0.2)

Nervous

Headache

10.2 (0.9)

10.6 (0.4)

11 (1.7)

14.7 (2)

Dizziness

2.7 (0.3)

2.7 (0)

3.6 (0.5)

3.7 (0.5)

Paresthesia

1.5 (0.3)

1.6 (0)

1.2 (0)

1.2 (0.2)

Respiratory

Upper Respiratory

Infection

1.8 (0)

3.9 (0)

1.9 (0)

0.7 (0)

Cough

0.3 (0)

0.8 (0)

1.2 (0)

1.7 (0)

Rhinorrhea

0 (0)

1.6 (0)

0.2 (0)

0.2 (0)

Sneezing

0 (0)

1.6 (0)

0 (0)

0 (0)

Skin

Rash

0.9 (0)

2 (0)

0.2 (0)

0.2 (0)

Flushing

0.9 (0.3)

3.9 (0)

5.3 (0.7)

6.9 (1.2)

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

1 of 2 episodes of elevated serum transaminases decreased once drug was discontinued in clinical

studies; no follow-up was available for the other patient.

OVERDOSAGE

Oral doses of 240 mg/kg and 264 mg/kg in male and female mice, respectively, and 2390 mg/kg and

2250 mg/kg in male and female rats, respectively, caused significant lethality.

In a suicide attempt, one patient took 150 mg felodipine together with 15 tablets each of atenolol and

spironolactone and 20 tablets of nitrazepam. The patient’s blood pressure and heart rate were normal on

admission to hospital; he subsequently recovered without significant sequelae.

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and

possibly bradycardia.

If severe hypotension occurs, symptomatic treatment should be instituted. The patient should be placed

supine with the legs elevated. The administration of intravenous fluids may be useful to treat

hypotension due to overdosage with calcium antagonists. In case of accompanying bradycardia, atropine

(0.5 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 poison-control centers are listed in the Physicians' Desk

Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-

Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-

drug interactions, and unusual drug kinetics in your patient.

DOSAGE AND ADMINISTRATION

The recommended starting dose is 5 mg once a day. Depending on the patient’s response, the dosage

can be decreased to 2.5 mg or increased to 10 mg once a day. These adjustments should occur generally

at intervals of not less than 2 weeks. The recommended dosage range is 2.5 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.

Geriatric Use

Patients over 65 years of age are likely to develop higher plasma concentrations of felodipine (see

CLINICAL PHARMACOLOGY). In general, dose selection for an elderly patient should be cautious,

usually starting at the low end of the dosing range (2.5 mg daily). Elderly patients should have their

blood pressure closely monitored during any dosage adjustment.

Patients with Impaired Liver Function

Patients with impaired liver function may have elevated plasma concentrations of felodipine and may

respond to lower doses of felodipine extended-release tablets; therefore, patients should have their

blood pressure monitored closely during dosage adjustment of felodipine extended-release tablets (see

CLINICAL PHARMACOLOGY).

HOW SUPPLIED

Product: 71335-1318

NDC: 71335-1318-1 30 TABLET, FILM COATED, EXTENDED RELEASE in a BOTTLE

Felodipine ER 5mg Tablet

FELODIPINE

felodipine tablet, film coated, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:71335-1318 (NDC:57237-10 9 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

FELO DIPINE (UNII: OL9 6 1R6 O2C) (FELODIPINE - UNII:OL9 6 1R6 O2C)

FELODIPINE

5 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

ALUMINUM SILICATE (UNII: T1FAD4SS2M)

HYDRO XYPRO PYL CELLULO SE ( 16 0 0 0 0 0 WAMW) (UNII: RFW2ET6 71P)

HYPRO MELLO SE 2 9 10 ( 50 MPA.S) (UNII: 1IVH6 78 16 N)

HYPRO MELLO SE 2 2 0 8 ( 10 0 MPA.S) (UNII: B1QE5P712K)

HYPRO MELLO SE 2 9 10 ( 6 MPA.S) (UNII: 0 WZ8 WG20 P6 )

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

PO LYETHYLENE GLYCO L 6 0 0 0 (UNII: 30 IQX730 WE)

PO LYO XYL 4 0 HYDRO GENATED CASTO R O IL (UNII: 7YC6 8 6 GQ8 F)

PRO PYL GALLATE (UNII: 8 D4SNN7V9 2)

SO DIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

Product Characteristics

Color

PINK

S core

no sco re

S hap e

ROUND (Bico nvex)

S iz e

11mm

Flavor

Imprint Code

X;16

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:71335-1318 -1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /28 /20 19

Marketing Information

Bryant Ranch Prepack

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 3417

0 1/17/20 13

Labeler -

Bryant Ranch Prepack (171714327)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Bryant Ranch Prepack

171714327

REPACK(71335-1318 ) , RELABEL(71335-1318 )

Revised: 9/2019

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