Felodip

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FELODIP (Felodip)

Composition:

Active substance: felodipine;

One tablet contains 2.5 mg or 5 mg or 10 mg of felodipine;

Excipients: lactose monohydrate, microcrystalline cellulose, hypromellose, povidone, propyl gallate, colloidal anhydrous silicon dioxide, magnesium stearate;

Coating of 2.5 mg tablet: hypromellose, yellow iron oxide (E 172), titanium dioxide (E 171), talc, propylene glycol;

Coating of 5 mg and 10 mg tablets: hypromellose, red iron oxide (E 172), yellow iron oxide (E 172), titanium dioxide (E 171), talc, propylene glycol.

Pharmaceutical form. Modified-release tablets.

Main physicochemical properties:

2.5 mg tablets: coated tablets, yellow in color, round, biconvex, 9 mm in diameter, with the imprint «2.5» on one side;

5 mg tablets: coated tablets, light pink in color, round, biconvex, 9 mm in diameter, with the imprint «5» on one side;

10 mg tablets: coated tablets, red-brown in color, round, biconvex, 9 mm in diameter, with the imprint «10» on one side.

Pharmacotherapeutic group. Selective calcium channel blockers with predominant vascular effect. Dihydropyridine derivatives. ATC code C08CA02.

Pharmacological Properties

Pharmacodynamics

Felodipine is a vasoselective calcium channel blocker that reduces arterial blood pressure by decreasing peripheral vascular resistance. At therapeutic doses, felodipine selectively affects smooth muscles of arterioles and does not exert a direct effect on myocardial contractility or cardiac conduction. The drug does not influence smooth muscles of veins or adrenergic vasomotor mechanisms; therefore, felodipine administration is not associated with symptoms of orthostatic hypotension. Felodipine has its own moderate natriuretic and diuretic effect and thus does not cause fluid retention in the body.

Felodipine is effective in various degrees of arterial hypertension. It can be used as monotherapy or in combination with other antihypertensive agents (e.g., β-blockers, diuretics, or angiotensin-converting enzyme (ACE) inhibitors) to enhance antihypertensive effects. Felodipine reduces both systolic and diastolic blood pressure and can be prescribed in cases of isolated systolic hypertension. The antihypertensive efficacy of felodipine is preserved even when used concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs).

Felodipine exerts antianginal and anti-ischemic effects by influencing the balance between myocardial oxygen supply and demand. Felodipine reduces resistance in coronary vessels. Blood flow through coronary vessels and myocardial oxygenation are also enhanced due to dilation of epicardial arteries and arterioles. Felodipine effectively prevents the formation and development of coronary artery spasm. The reduction in systemic arterial pressure induced by felodipine decreases left ventricular afterload and reduces myocardial oxygen demand.

Felodipine improves exercise tolerance and reduces the frequency of angina attacks in patients with stable exertional angina. In patients with stable angina, felodipine can be prescribed either as monotherapy or in combination with β-adrenergic receptor blockers.

Felodipine is an effective agent well tolerated by adult patients regardless of age or race, including those with concomitant conditions such as congestive heart failure, bronchial asthma and other obstructive lung diseases, renal insufficiency, diabetes mellitus, gout, hyperlipidemia, Raynaud's phenomenon, and patients after kidney transplantation. Felodipine does not affect glycemia or lipid profile.

Site and Mechanism of Action. The main pharmacodynamic characteristic of felodipine is its high degree of vascular selectivity. Myogenically active smooth muscles of resistance arterioles are particularly sensitive to the action of felodipine. Felodipine inhibits electrical and contractile activity of vascular smooth muscles by acting on calcium channels in the cell membrane.

Hemodynamic Effects. The primary hemodynamic effect of felodipine is a reduction in total peripheral vascular resistance, resulting in decreased arterial blood pressure. This effect is dose-dependent. Generally, blood pressure reduction begins within 2 hours after a single dose and lasts for at least 24 hours, with a trough/peak (T/R) ratio significantly exceeding 50%. A positive correlation exists between plasma felodipine concentration and reductions in peripheral vascular resistance and arterial blood pressure.

Cardiac Effects. At therapeutic doses, felodipine does not affect myocardial contractility, atrioventricular conduction, or the refractory period of the atrioventricular node. Antihypertensive therapy with felodipine is associated with significant regression of pre-existing left ventricular hypertrophy.

Renal Effects. Felodipine has a mild natriuretic and diuretic effect due to reduced tubular reabsorption of sodium. Felodipine does not affect daily excretion of potassium or albumin. Renal vascular resistance decreases after felodipine administration. Normal glomerular filtration rate (GFR) remains unchanged. In patients with impaired renal function, GFR may increase during treatment with felodipine.

In patients receiving cyclosporine after kidney transplantation, felodipine reduces arterial blood pressure, improves renal blood flow, and increases GFR. Felodipine may improve graft function in the early stages after transplantation.

Effective reduction of high arterial pressure is particularly beneficial for patients with diabetes mellitus.

Clinical Efficacy. In the HOT (Hypertension Optimal Treatment) study, the relationship between major cardiovascular events (such as acute myocardial infarction, stroke, and cardiovascular mortality) and target diastolic blood pressure levels of ≤ 90 mm Hg, ≤ 85 mm Hg, and ≤ 80 mm Hg, as well as achieved blood pressure levels, was evaluated, with felodipine used as baseline therapy.

A total of 18,790 hypertensive patients (diastolic blood pressure 100–115 mm Hg), aged 50–80 years, were followed for a mean duration of 3.8 years (range 3.3 to 4.9 years). Felodipine was used either as monotherapy or in combination with a β-blocker and/or ACE inhibitor and/or diuretic. The positive outcomes of the study included reductions in systolic and diastolic blood pressure to 139 and 83 mm Hg, respectively.

In the STOP-2 (Swedish Trial in Old Patients with Hypertension-2) study, which included 6,614 patients aged 70 to 84 years, calcium channel blockers of the dihydropyridine class (felodipine and isradipine) demonstrated a preventive effect on mortality and morbidity due to cardiovascular diseases comparable to that of other widely used classes of antihypertensive drugs—ACE inhibitors, β-blockers, and diuretics.

Pharmacokinetics

Absorption. Felodipine is completely absorbed from the gastrointestinal tract after oral administration of modified-release tablets. Bioavailability in humans is approximately 15% and does not depend on the administered dose within the therapeutic range. Due to the specific formulation, the modified release of felodipine prolongs the absorption phase and ensures a uniform plasma concentration over 24 hours. When administered as a prolonged-release formulation, maximum plasma concentration (t_max) is reached within 3–5 hours. Concomitant intake with a fatty meal increases the rate of absorption without altering the extent of absorption.

Distribution. Approximately 99% of felodipine is bound to plasma proteins, primarily to albumins. The volume of distribution at steady state is 10 L/kg.

Metabolism. Felodipine is primarily metabolized in the liver via the cytochrome P450 3A4 (CYP3A4) enzyme system; all its metabolites are inactive. Felodipine belongs to drugs with high clearance, averaging 1200 mL/min. With long-term use, no significant drug accumulation occurs.

Plasma concentrations of felodipine are higher in elderly patients and in patients with impaired liver function compared to younger individuals. The pharmacokinetics of felodipine are not altered in patients with renal impairment, including those undergoing hemodialysis.

Elimination. The elimination half-life of felodipine is approximately 25 hours, and steady-state concentration is achieved within 5 days. With long-term administration, no accumulation of the active substance occurs. Approximately 70% of the administered dose is excreted in urine and the remainder in feces, primarily as metabolites. Less than 0.5% of the administered dose is excreted unchanged in urine.

Linearity/Non-linearity. Plasma concentrations are directly proportional to the dose within the therapeutic range of 2.5–10 mg.

Clinical characteristics.

Indications.

Arterial hypertension.

Prophylactic treatment of chronic stable angina.

Contraindications.

• Hypersensitivity to felodipine and to other dihydropyridines (theoretical risk of cross-reactivity) or to any of the excipients.

− Decompensated heart failure.

• Unstable angina.

− Acute myocardial infarction.

• Dynamic obstruction of the left ventricular outflow tract.

− Severe aortic/mitral stenosis.

Interaction with other medicinal products and other forms of interactions.

Felodipine is metabolized in the liver via the cytochrome P450 3A4 (CYP3A4) enzyme system. Concomitant administration of substances that interact with the cytochrome P450 3A4 enzyme system may affect plasma levels of felodipine.

Enzyme interactions

Medicinal products that are inhibitors or inducers of the cytochrome P450 3A4 isoenzyme may affect plasma levels of felodipine.

Interactions leading to increased plasma concentration of felodipine

Enzyme inhibitors such as cimetidine, ranitidine, erythromycin, itraconazole, ketoconazole, anti-HIV protease inhibitors (e.g., ritonavir), quinidine, and certain flavonoids present in grapefruit juice increase the plasma concentration of felodipine. When administered concomitantly with the potent CYP3A4 inhibitor itraconazole, Cmax and AUC of felodipine increased by 8 and 6 times, respectively. When co-administered with erythromycin, Cmax and AUC of felodipine increased by 2.5 times, while cimetidine increased Cmax and AUC of felodipine by approximately 55%. Combinations of felodipine with potent CYP3A4 inhibitors should be avoided. If clinically significant adverse effects due to excessive felodipine effects occur when the drug is combined with potent CYP3A4 inhibitors, dose adjustment of felodipine and/or discontinuation of the CYP3A4 inhibitor is recommended.

Interactions leading to decreased plasma concentration of felodipine

Enzyme inducers such as phenytoin, carbamazepine, rifampicin, barbiturates, efavirenz, nevirapine, and St John's wort (Hypericum perforatum) may reduce plasma concentrations of felodipine; therefore, patients taking these drugs may require higher doses. When felodipine was administered concomitantly with carbamazepine, phenytoin, or phenobarbital, Cmax of felodipine decreased by 82% and AUC by 96%. Combinations of felodipine with potent CYP3A4 inducers should be avoided.

If inadequate clinical response occurs due to reduced felodipine concentrations when used in combination with potent CYP3A4 inducers, dose adjustment of felodipine and/or discontinuation of the CYP3A4 inducer is recommended.

Additional interactions

Felodipine may increase the concentration of tacrolimus. When felodipine and tacrolimus are used concomitantly, plasma concentrations of tacrolimus should be monitored and its dose adjusted accordingly.

Felodipine does not affect the plasma concentration of cyclosporine.

Grapefruit juice increases the plasma level and bioavailability of felodipine due to the presence of flavonoids; therefore, it should not be used together with felodipine.

Antihypertensive agents prolong the hypotensive effect of felodipine.

Sympathomimetics reduce the effect of felodipine.

Dose adjustment is not required when felodipine is used concomitantly with digoxin.

Felodipine does not affect the free fraction of other drugs highly bound to plasma proteins, such as warfarin.

Special precautions for use.

The efficacy and safety of felodipine in the treatment of hypertensive crisis have not been studied.

Like other vasodilators, the medicinal product Felodip may rarely cause significant arterial hypotension with tachycardia, which in sensitive patients may lead to myocardial ischemia.

Felodipine is metabolized in the liver. Therefore, higher therapeutic concentrations and an enhanced response to treatment may be expected in patients with significantly impaired liver function (see section "Dosage and administration").

Concomitant use of potent inducers or inhibitors of the CYP3A4 isoenzymes may lead to significant decreases or increases in plasma levels of felodipine, respectively. Therefore, such combinations should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Mild gingival hyperplasia has been reported in patients with pronounced gingivitis/periodontitis. This can be prevented by maintaining careful oral hygiene.

The medicinal product Felodip should be administered with caution in patients with severe left ventricular dysfunction.

The product contains lactose; therefore, it should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy

Felodip is contraindicated during pregnancy. Non-clinical studies of reproductive toxicity have shown effects on fetal development related to the pharmacological action of felodipine.

Breastfeeding

Felodip may pass into breast milk, but it is unknown whether it has a negative effect on newborns. Due to limited safety data on the use of the drug in infants who are breastfed, felodipine should not be used during breastfeeding.

Fertility

There are no data on the effect of felodipine on fertility. Studies in rats have demonstrated evidence of an effect on fetal development but no effect on fertility when therapeutic doses were administered.

Ability to affect reaction speed when driving or operating machinery.

Felodipine has negligible or moderate influence on the ability to drive or operate machinery. If patients experience headache, nausea, dizziness, or weakness during treatment, their reaction speed may be impaired. Particular caution should be exercised at the beginning of therapy.

Method of Administration and Dosage.

Adults:

Arterial hypertension.

The dosage regimen is always determined individually.

Treatment is initiated at a dose of 5 mg once daily. Depending on the clinical response, the dose may be reduced to 2.5 mg or increased to 10 mg per day. If necessary, another antihypertensive agent may be added. The standard maintenance dose is 5 mg once daily.

Angina pectoris.

The dosage regimen is always determined individually.

Treatment is initiated at a dose of 5 mg once daily. If necessary, this dose may be increased to 10 mg once daily.

Felodipine may be used in combination with β-blockers, ACE inhibitors, or diuretics. The antihypertensive effects of these agents may be additive; therefore, combination therapy should be used with caution to avoid hypotension.

Elderly patients: treatment should be initiated with the lowest possible dose.

Patients with renal impairment: patients with impaired renal function do not require dose adjustment.

Patients with hepatic impairment: in patients with impaired liver function, increased plasma concentrations of felodipine may occur. Such patients may be more sensitive to treatment and may respond to lower doses.

Method of administration: the drug should preferably be taken in the morning, before meals or after a light breakfast low in fat and carbohydrates. Tablets must not be chewed, divided, or crushed, in order to preserve their modified-release properties. Tablets should be swallowed whole with water.

Children. Due to limited experience in pediatric practice, the drug should not be prescribed to children.

Overdose.

Symptoms. Overdose may cause excessive peripheral vasodilation leading to marked arterial hypotension, which may sometimes be accompanied by bradycardia.

Treatment. If possible, administer activated charcoal or perform gastric lavage within 1 hour after ingestion of an excessive dose. Symptomatic treatment is indicated in cases of severe arterial hypotension. The patient should be placed in a supine position with elevated legs. In case of bradycardia, administer atropine 0.5–1 mg intravenously. If this is insufficient, restore blood plasma volume by infusion, e.g. glucose, 0.9% sodium chloride solution, or dextran. If these measures fail to normalize the clinical condition, sympathomimetics with predominant α1-adrenoceptor activity may be used.

Adverse Reactions

As with other calcium channel blockers, the drug may cause facial flushing, headache, palpitations, dizziness, and fatigue. Most of these reactions are dose-dependent and usually occur at the beginning of treatment or when the dose is increased. Typically, they are transient. Also possible, depending on the dose, are ankle swelling due to precapillary vasodilation rather than fluid retention. Gingival hyperplasia may occur in patients with gingivitis or periodontitis; this can be prevented by maintaining careful oral hygiene.

Immune system disorders: Hypersensitivity reactions (e.g., urticaria and angioneurotic edema).

Nervous system disorders: Headache, sleep disturbances, somnolence, dizziness, paresthesia, restlessness, irritability, confusion, depression.

Respiratory system disorders: Dyspnea, epistaxis.

Cardiovascular system disorders: Worsening of angina symptoms (particularly at the beginning of treatment). Mainly in patients with symptomatic ischemic heart disease: syncope, palpitations, tachycardia, myocardial infarction, hot flushes, peripheral edema (the degree of ankle swelling is dose-dependent), arterial hypotension.

Reproductive system disorders: Impotence/sexual dysfunction.

Urinary system disorders: Frequent urination.

Gastrointestinal disorders: Nausea, gingivitis, gingival hyperplasia, abdominal pain, vomiting, periodontitis, diarrhea, constipation, dry mouth.

Hepatobiliary disorders: Increased liver enzyme levels, cholestatic hepatitis.

Skin and subcutaneous tissue disorders: Erythema, skin rash, pruritus, photosensitivity, angioneurotic edema, erythema multiforme, nodular erythema, leukocytoclastic vasculitis.

Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, muscle tremor.

General disorders and administration site conditions: Increased fatigue, increased body temperature.

Shelf life. 4 years.

Storage conditions. Store at a temperature not exceeding 25°C. Keep out of reach of children.

Packaging. 10 tablets per blister; 3 or 10 blisters per carton.

Prescription category. Prescription only.

Manufacturer.

Merckle GmbH.

Manufacturer's address and location of operations.

Ludwig-Merckle-Strasse 3, 89143 Blaubeuren, Germany.