FELODIPINE Extended-release tablet Ref.[108211] Active ingredients: Felodipine

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

^* Patients in titration studies may have been exposed to more than one dose level of Felodipine.

Adverse events that occurred in 0.5 up to 1.5% of patients who received Felodipine 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 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 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.

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 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; 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. (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 2–3 weeks of the initiation of treatment.

Patients should be instructed to take Felodipine 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 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.

CYP3A4 Inhibitors: 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:

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

Erythromycin: Co-administration 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: Co-administration 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: 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_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 the pharmacokinetics of digoxin in patients with heart failure was 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.

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/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.

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.

^** Based on patient weight of 50 kg

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.

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.

Safety and effectiveness in pediatric patients have not been established.

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.