FELODIPINEEXTENDED-RELEASE TABLETS (Page 2 of 5)

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 given once daily as monotherapy are shown in the table below:

MEAN REDUCTIONS IN BLOOD PRESSURE (mmHg)^*

Dose	N	Systolic/Diastolic Mean Peak Response	Mean Trough Response	Trough/Peak Ratios (%s)
* Placebo response subtracted ** Different number of patients available for peak and trough measurements
Study 1 (8 weeks)
2.5 mg	68	9.4/4.7	2.7/2.5	29/53
5 mg	69	9.5/6.3	2.4/3.7	25/59
10 mg	67	18.0/10.8	10.0/6.0	56/56
Study 2 (4 weeks)
10 mg	50	5.3/7.2	1.5/3.2	33/40**
20 mg	50	11.3/10.2	4.5/3.2	43/34**

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.

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 2-3 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

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.