Felodipine: Package Insert and Label Information

FELODIPINE- felodipine tablet, extended release
Yiling Pharmaceutical Inc.

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 empirical formula is C 18 H 19 Cl 2 NO 4 and its structural formula is:

Chemical Structure
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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, USP provide extended release of felodipine. They are available as tablets containing 2.5 mg, 5 mg, or 10 mg of felodipine for oral administration.

Inactive ingredients for core tablets are: anhydrous lactose, butylated hydroxyanisole, butylated hydroxytoluene, colloidal silicon dioxide, hypromellose, polyoxyl 40 hydrogenated castor oil, microcrystalline cellulose, povidone K30 and sodium stearyl fumarate.

Film coating materials of 2.5mg: ferrosoferric oxide, hypromellose, iron oxide red, iron oxide yellow, maltodextrin, medium chain triglycerides, polydextrose, talc and titanium dioxide.

Film coating materials of 5mg: ferrosoferric oxide, hypromellose, iron oxide red, iron oxide yellow, maltodextrin, medium chain triglycerides, polydextrose, talc and titanium dioxide.

Film coating materials of 10mg: ferrosoferric oxide, hypromellose, iron oxide red, iron oxide yellow, maltodextrin, medium chain triglycerides, polydextrose, talc and titanium dioxide.

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, is approximately 20%. Mean peak concentrations following the administration of Felodipine 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 (EC 50 ) [4–6 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 were 23 and 7 nmol/L. Since the EC 50 for felodipine is 4 to 6 nmol/L, a 5- to 10-mg dose of Felodipine 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 14 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 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 is influenced by the presence of food. When administered either with a high fat or carbohydrate diet, Cmax is increased by approximately 60%; AUC is unchanged. When Felodipine was administered after a light meal (orange 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. 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 ae. 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, 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 40–50% 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 5–10 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 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 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 18/10.8 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, 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 (eg, 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 is 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 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.

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