FELODIPINEEXTENDED-RELEASE TABLETS

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Overview

What is FELODIPINEEXTENDED-RELEASE TABLETS?

Felodipine is a calcium antagonist (calcium channel blocker). Felodipine is a dihydropyridine derivative that is chemically described as ± ethyl methyl 4-(2, 3-dichlorophenyl)-1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylate. Its empirical formula is CHClNO and its structural formula is:

Felodipine is a slightly yellowish, crystalline powder with a molecular weight of 384.26. It is insoluble in water and is freely soluble in dichloromethane and ethanol. Felodipine is a racemic mixture.

Felodipine extended-release tablets provide extended release of felodipine. They are available as tablets containing 2.5 mg, 5 mg, or 10 mg at felodipine for oral administration. In addition to the active ingredient felodipine, the tablets contain the following inactive ingredients: Felodipine extended-release tablets 2.5 mg — hydroxypropyl cellulose, lactose, FD&C Blue 2, sodium stearyl fumarate, titanium dioxide, yellow iron oxide, and other ingredients. Felodipine extended-release tablets 5 mg and 10 mg—cellulose, red and yellow oxide, lactose, polyethylene glycol, sodium stearyl fumarate, titanium dioxide, and other ingredients.

What does FELODIPINEEXTENDED-RELEASE TABLETS look like?

What are the available doses of FELODIPINEEXTENDED-RELEASE TABLETS?

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What should I talk to my health care provider before I take FELODIPINEEXTENDED-RELEASE TABLETS?

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How should I use FELODIPINEEXTENDED-RELEASE TABLETS?

Felodipine extended-release tablets are indicated for the treatment of hypertension. Felodipine extended-release tablets may be used alone or concomitantly 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 - 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 ). 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 ). Felodipine extended-release tablets should be swallowed whole and not crushed or chewed.

What interacts with FELODIPINEEXTENDED-RELEASE TABLETS?

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

What are the warnings of FELODIPINEEXTENDED-RELEASE TABLETS?

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What are the precautions of FELODIPINEEXTENDED-RELEASE TABLETS?

General

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 )

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 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 and )

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 2-3 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 are 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

Felodipine is metabolized by CYP3A4. Co-administration of CYP3A4 inhibitors (eg., 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:

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.

When given concomitantly with felodipine extended-release tablets the pharmacokinetics of digoxin in patients with heart failure were not significantly altered.

In a pharmacokinetic study, maximum plasma concentrations of felodipine were considerably lower in epileptic patients on long-term anticonvulsant therapy (eg, 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.

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.

In healthy subjects there were no clinically significant interactions when felodipine was given concomitantly with indomethacin or spironolactone.

See

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

Felodipine did not display any mutagenic activity in the Ames microbial mutagenicity test or in the mouse lymphoma forward mutation assay. No clastogenic potential was seen in the mouse micronucleus test at oral doses up to 2500 mg/kg (1100 times the maximum recommended human dose on a mg/m basis) or in a human lymphocyte chromosome aberration assay.

A fertility study in which male and female rats were administered doses of 3.8, 9.6 or 26.9 mg/kg/day (up to 24 times the maximum recommended human dose on a mg/m basis) showed no significant effect of felodipine on reproductive performance.

Pregnancy

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 ). 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.

What are the side effects of FELODIPINEEXTENDED-RELEASE TABLETS?

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 ).

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: Chest pain, facial edema, flu-like illness; tachycardia, premature beats; Abdominal pain, diarrhea, vomiting, dry mouth, flatulence, acid regurgitation; Gynecomastia; ALT (SGPT) increased; Arthralgia, back pain, leg pain, foot pain, muscle cramps, myalgia, arm pain, knee pain, hip pain; Insomnia, depression, anxiety disorders, irritability, nervousness, somnolence, decreased libido; Dyspnea, pharyngitis, bronchitis, influenza, sinusitis, epistaxis, respiratory infection; Angioedema, contusion, erythema, urticaria, Visual disturbances; Impotence, urinary frequency, urinary urgency, dysuria, polyuria.

Gingival Hyperplasia

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)
Array
Body System	Placebo	2.5 mg	5 mg	10 mg
Adverse Events	N = 334	N = 255	N = 581	N = 408

Peripheral Edema	3.3 (0.0)	2.0 (0.0)	8.8 (2.2)	17.4 (2.5)
Asthenia	3.3 (0.0)	3.9 (0.0)	3.3 (0.0)	2.2 (0.0)
Warm Sensation	0.0 (0.0)	0.0 (0.0)	0.9 (0.2)	1.5 (0.0)

Palpitation	2.4 (0.0)	0.4 (0.0)	1.4 (0.3)	2.5 (0.5)

Nausea	1.5 (0.9)	1.2 (0.0)	1.7 (0.3)	1.0 (0.7)
Dyspepsia	1.2 (0.0)	3.9 (0.0)	0.7 (0.0)	0.5 (0.0)
Constipation	0.9 (0.0)	1.2 (0.0)	0.3 (0.0)	1.5 (0.2)

Headache	10.2 (0.9)	10.6 (0.4)	11.0 (1.7)	14.7 (2.0)
Dizziness	2.7 (0.3)	2.7 (0.0)	3.6 (0.5)	3.7 (0.5)
Paresthesia	1.5 (0.3)	1.6 (0.0)	1.2 (0.0)	1.2 (0.2)

Upper Respiratory Infection	1.8 (0.0)	3.9 (0.0)	1.9 (0.0)	0.7 (0.0)
Cough	0.3 (0.0)	0.8 (0.0)	1.2 (0.0)	1.7 (0.0)
Rhinorrhea	0.0 (0.0)	1.6 (0.0)	0.2 (0.0)	0.2 (0.0)
Sneezing	0.0 (0.0)	1.6 (0.0)	0.0 (0.0)	0.0 (0.0)

Rash	0.9 (0.0)	2.0 (0.0)	0.2 (0.0)	0.2 (0.0)
Flushing	0.9 (0.3)	3.9 (0.0)	5.3 (0.7)	6.9 (1.2)

Clinical Laboratory Test Findings

Serum Electrolytes

Serum Glucose

Liver Enzymes

What should I look out for while using FELODIPINEEXTENDED-RELEASE TABLETS?

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

What might happen if I take too much FELODIPINEEXTENDED-RELEASE TABLETS?

Oral doses of 240 mg/kg and 264 mg/kg in male and female mice, respectively, and 2390 mg/kg and 2250 mg/kg in male and female rats, respectively, caused significant lethality.

In a suicide attempt, one patient took 150 mg felodipine together with 15 tablets each of atenolol and spironolactone and 20 tablets of nitrazepam. The patient's blood pressure and heart rate were normal on admission to hospital; he subsequently recovered without significant sequelae.

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

If severe hypotension occurs, symptomatic treatment should be instituted. The patient should be placed supine with the legs elevated. The administration of intravenous fluids may be useful to treat hypotension due to overdosage with calcium antagonists. In case of accompanying bradycardia, atropine (0.5-1 mg) should be administered intravenously. Sympathomimetic drugs may also be given if the physician feels they are warranted.

It has not been established whether felodipine can be removed from the circulation by hemodialysis.

To obtain up-to-date information about the treatment of overdose, consult your Regional Poison-Control Center. Telephone numbers of certified poison-control centers are listed in the . In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient.

How should I store and handle FELODIPINEEXTENDED-RELEASE TABLETS?

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP] .No.3584 — Felodipine extended-release tablets, 2.5 mg, are sage green, round convex tablets, with code 450 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-435-01 bottles of 100No.3585 — Felodipine extended-release tablets, 5 mg, are light red-brown, round convex tablets, with code 451 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-436-01 bottles of 100No.3586 — Felodipine extended-release tablets, 10 mg, are red-brown, round convex tablets, with code 452 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-437-01 bottles of 100No.3584 — Felodipine extended-release tablets, 2.5 mg, are sage green, round convex tablets, with code 450 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-435-01 bottles of 100No.3585 — Felodipine extended-release tablets, 5 mg, are light red-brown, round convex tablets, with code 451 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-436-01 bottles of 100No.3586 — Felodipine extended-release tablets, 10 mg, are red-brown, round convex tablets, with code 452 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-437-01 bottles of 100No.3584 — Felodipine extended-release tablets, 2.5 mg, are sage green, round convex tablets, with code 450 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-435-01 bottles of 100No.3585 — Felodipine extended-release tablets, 5 mg, are light red-brown, round convex tablets, with code 451 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-436-01 bottles of 100No.3586 — Felodipine extended-release tablets, 10 mg, are red-brown, round convex tablets, with code 452 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-437-01 bottles of 100No.3584 — Felodipine extended-release tablets, 2.5 mg, are sage green, round convex tablets, with code 450 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-435-01 bottles of 100No.3585 — Felodipine extended-release tablets, 5 mg, are light red-brown, round convex tablets, with code 451 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-436-01 bottles of 100No.3586 — Felodipine extended-release tablets, 10 mg, are red-brown, round convex tablets, with code 452 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-437-01 bottles of 100No.3584 — Felodipine extended-release tablets, 2.5 mg, are sage green, round convex tablets, with code 450 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-435-01 bottles of 100No.3585 — Felodipine extended-release tablets, 5 mg, are light red-brown, round convex tablets, with code 451 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-436-01 bottles of 100No.3586 — Felodipine extended-release tablets, 10 mg, are red-brown, round convex tablets, with code 452 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-437-01 bottles of 100No.3584 — Felodipine extended-release tablets, 2.5 mg, are sage green, round convex tablets, with code 450 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-435-01 bottles of 100No.3585 — Felodipine extended-release tablets, 5 mg, are light red-brown, round convex tablets, with code 451 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-436-01 bottles of 100No.3586 — Felodipine extended-release tablets, 10 mg, are red-brown, round convex tablets, with code 452 on one side and PLENDIL on the other. They are supplied as follows:NDC 63304-437-01 bottles of 100

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Felodipine is a member of the dihydropyridine class of calcium channel antagonists (calcium channel blockers). It reversibly competes with nitrendipine and/or other calcium channel blockers for dihydropyridine binding sites, blocks voltage-dependent Ca currents in vascular smooth muscle and cultured rabbit atrial cells, and blocks potassium-induced contracture of the rat portal vein.

In vitro

in vitro

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 ). 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.

Non-Clinical Toxicology

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

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 ).

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: Chest pain, facial edema, flu-like illness; tachycardia, premature beats; Abdominal pain, diarrhea, vomiting, dry mouth, flatulence, acid regurgitation; Gynecomastia; ALT (SGPT) increased; Arthralgia, back pain, leg pain, foot pain, muscle cramps, myalgia, arm pain, knee pain, hip pain; Insomnia, depression, anxiety disorders, irritability, nervousness, somnolence, decreased libido; Dyspnea, pharyngitis, bronchitis, influenza, sinusitis, epistaxis, respiratory infection; Angioedema, contusion, erythema, urticaria, Visual disturbances; Impotence, urinary frequency, urinary urgency, dysuria, polyuria.

Gingival Hyperplasia

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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