Felodipine

Torrent Pharmaceuticals Limited
Torrent Pharma, Inc.

Felodipine Extended-Release Tablets, USPRx only

FULL PRESCRIBING INFORMATION: CONTENTS*

• FELODIPINE DESCRIPTION
• CLINICAL PHARMACOLOGY
• FELODIPINE INDICATIONS AND USAGE
• FELODIPINE CONTRAINDICATIONS
• PRECAUTIONS
• Information for Patients
• Drug Interactions
• Carcinogenesis, Mutagenesis, Impairment of Fertility
• Pregnancy
• Nursing Mothers
• Pediatric Use
• Geriatric Use
• FELODIPINE ADVERSE REACTIONS
• OVERDOSAGE
• FELODIPINE DOSAGE AND ADMINISTRATION
  • Geriatric Use
• HOW SUPPLIED
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

FELODIPINE 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 C₁₈H₁₉Cl₂NO₄ 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 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: colloidal silicon dioxide, hydroxy propyl cellulose, hypromellose, lactose anhydrous, magnesium oxide, microcrystalline cellulose, polyoxyl 40 hydrogenated castor oil, propyl gallate, propylene glycol, sodium stearyl fumarate, talc, titanium dioxide and additional agents listed below:

2.5 mg tablets: Ferric oxide yellow and lake of indigo carmine

5 and 10 mg tablets: Ferric oxide red and ferric oxide yellow

Meets USP Dissolution Test 3.

CLINICAL PHARMACOLOGY

FELODIPINE INDICATIONS AND USAGE

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.

FELODIPINE CONTRAINDICATIONS

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

PRECAUTIONS

Information for Patients

Patients should be instructed to take felodipine extended-release 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 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. 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 C_max, and 2-fold prolongation in the half-life of felodipine.

Erythromycin

Coadministration of felodipine with erythromycin resulted in approximately 2.5-fold increase in the AUC and C_max, and about 2-fold prolongation in the half-life of felodipine.

Grapefruit Juice

Coadministration of felodipine with grapefruit juice resulted in more than 2-fold increase in the AUC and C_max, 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 C_max, 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_max 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 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

Pharmacokinetics and Metabolism

Following oral administration, felodipine is almost completely absorbed and undergoes extensive first-pass metabolism. The systemic bioavailability of felodipine 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_1/2.

Following oral administration of the immediate-release formulation, the plasma level of felodipine also declined polyexponentially with a mean terminal t_1/2 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 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 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.

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 times¹ 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 times¹ 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 times¹ 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 times¹ 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 times¹ the maximum recommended human dose on a mg/m² basis) showed no significant effect of felodipine on reproductive performance.

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 times¹ 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 times¹ the maximum human dose on a mg/m² 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/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 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.

¹ 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.

FELODIPINE ADVERSE REACTIONS

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 extended-release 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, 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, 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 (N = 861) as Monotherapy without Regard to Causality (Incidence of discontinuations shown in parentheses)

Adverse events that occurred in 0.5% up to 1.5% of patients who received felodipine extended-release 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 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 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.

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 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 poison-control 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 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 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.

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

Felodipine Extended-Release Tablets, USP are available containing 2.5 mg, 5 mg or 10 mg of felodipine, USP.

The 2.5 mg tablet is a green-colored, round-shaped, biconvex film-coated tablets debossed with "32" on one side and "2.5" on other side.

They are available as follows:

Bottles of 30                           NDC 13668-132-30

Bottles of 90                           NDC 13668-132-90

Bottles of 100                         NDC 13668-132-01

Bottles of 500                         NDC 13668-132-05

Bottles of 1000                       NDC 13668-132-10

100 Unit dose Tablets            NDC 13668-132-74

The 5 mg tablet is a pink-colored, round-shaped, biconvex film-coated tablets debossed with "33" on one side and "5" on other side.

They are available as follows:

Bottles of 30                           NDC 13668-133-30

Bottles of 90                           NDC 13668-133-90

Bottles of 100                         NDC 13668-133-01

Bottles of 500                         NDC 13668-133-05

Bottles of 1000                       NDC 13668-133-10

100 Unit dose Tablets            NDC 13668-133-74

The 10 mg tablet is a reddish brown-colored, round-shaped, biconvex film-coated tablets debossed with "34" on one side and "10" on other side.

They are available as follows:

Bottles of 30                           NDC 13668-134-30

Bottles of 90                           NDC 13668-134-90

Bottles of 100                         NDC 13668-134-01

Bottles of 500                         NDC 13668-134-05

Bottles of 1000                       NDC 13668-134-10

100 Unit dose Tablets            NDC 13668-134-74

Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Protect from light.

Dispense in a tight, light-resistant container with a child-resistant closure.

Manufactured by:

TORRENT PHARMACEUTICALS LTD., Indrad-382 721, Dist. Mehsana, INDIA.

For:

TORRENT PHARMA INC., 5380 Holiday Terrace, Suite 40,

Kalamazoo, Michigan 49009.

      8031869                                                                                           Revised November 2011

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Felodipine Extended-Release Tablets, USP 2.5 mg

Felodipine Extended-Release Tablets, USP 5 mg

Felodipine Extended-Release Tablets, USP 10 mg