Plendil^® (Tablets) Instructions for Use

Marketing Authorization Holder

AstraZeneca AB (Sweden)

Manufactured By

AstraZeneca Pharmaceutical Co. Ltd. (China)

ATC Code

C08CA02 (Felodipine)

Active Substance

Felodipine (Rec.INN registered by WHO)

Dosage Forms

	Plendil®	Extended-release film-coated tablets, 2.5 mg: 30 pcs.
		Extended-release film-coated tablets, 5 mg: 30 pcs.
		Extended-release film-coated tablets, 10 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Extended-release film-coated tablets yellow, round, biconvex, with the letters “A” over “FL” engraved on one side and “2.5” on the other.

Excipients : hypromellose (hydroxypropyl methylcellulose) – 100 mg, lactose anhydrous – 28 mg, microcrystalline cellulose – 3 mg, macrogol glyceryl hydroxystearate – 2.5 mg, propyl gallate – 0.06 mg, sodium aluminosilicate – 47 mg, sodium stearyl fumarate – 3.9 mg.

Coating composition carnauba wax ~ 0.1 mg, yellow iron oxide – 0.15 mg, hypromellose – 4.9 mg, macrogol 6000 – 1.2 mg, titanium dioxide (E171) – 0.7 mg.

30 pcs. – plastic bottles (1) – cardboard boxes.

Extended-release film-coated tablets pink, round, biconvex, with the letters “A” over “Fm” engraved on one side and “5” on the other.

Excipients : hypromellose (hydroxypropyl methylcellulose) – 100 mg, lactose anhydrous – 28 mg, microcrystalline cellulose – 3 mg, macrogol glyceryl hydroxystearate – 5 mg, propyl gallate – 0.06 mg, sodium aluminosilicate – 47 mg, sodium stearyl fumarate – 4 mg.

Coating composition carnauba wax ~ 0.1 mg, reddish-brown iron oxide – 0.03 mg, yellow iron oxide – 0.01 mg, hypromellose – 5 mg, macrogol 6000 – 1.3 mg, titanium dioxide (E171) – 0.7 mg.

30 pcs. – plastic bottles (1) – cardboard boxes.

Extended-release film-coated tablets red-brown, round, biconvex, with the letters “A” over “FE” engraved on one side and “10” on the other.

Excipients : hypromellose (hydroxypropyl methylcellulose) – 100 mg, lactose anhydrous – 28 mg, microcrystalline cellulose – 3 mg, macrogol glyceryl hydroxystearate – 10 mg, propyl gallate – 0.06 mg, sodium aluminosilicate – 47 mg, sodium stearyl fumarate – 4.2 mg.

Coating composition carnauba wax ~ 0.1 mg, reddish-brown iron oxide – 0.1 mg, yellow iron oxide – 0.07 mg, hypromellose – 5.3 mg, macrogol 6000 – 1.3 mg, titanium dioxide (E171) – 0.6 mg.

30 pcs. – plastic bottles (1) – cardboard boxes.

Clinical-Pharmacological Group

Calcium channel blocker

Pharmacotherapeutic Group

BMCC (Bone Mineral Crystal Complex)

Pharmacological Action

Felodipine is a selective class II calcium channel blocker from the dihydropyridine derivative group. Like other dihydropyridine derivatives, Felodipine has a significantly higher affinity for calcium channels in arterial smooth muscle cells than for calcium channels in cardiomyocytes. By blocking calcium channels and disrupting the influx of calcium ions into arterial smooth muscle cells, it causes their dilation, reduces total peripheral resistance, and lowers blood pressure. It decreases the afterload on the heart.

It has virtually no depressant effect on myocardial contractility and conductivity, and causes a moderately pronounced reflex tachycardia. It increases coronary blood flow.

It reduces the influx of extracellular calcium into cardiomyocytes and smooth muscle cells of coronary and peripheral arteries; in high doses, it reduces the release of calcium ions from intracellular stores. It decreases the number of functioning channels without affecting their activation, inactivation, and recovery time. It uncouples the processes of excitation and contraction in the myocardium, mediated by tropomyosin and troponin, and in vascular smooth muscles, mediated by calmodulin.

In therapeutic doses, it normalizes the transmembrane calcium current, which is impaired in a number of pathological conditions, primarily in arterial hypertension. It lowers blood pressure due to vasodilation and reduction of total peripheral resistance. It does not affect venous tone and adrenergic vasomotor innervation, therefore it does not cause orthostatic hypotension.

It has a dose-dependent anti-ischemic effect. It enhances coronary blood flow, improves blood supply to ischemic areas of the myocardium without the development of the “steal” phenomenon, activates collateral function, protects against reperfusion complications, and slightly increases heart rate. By dilating peripheral arteries, it reduces afterload.

It has almost no effect on the sinoatrial and AV nodes. It has virtually no negative inotropic effect (the reflex increase in heart rate in response to vasodilation masks the negative inotropic effect).

It enhances renal blood flow, has a moderate natriuretic and diuretic effect.

The effect begins within 2-5 hours and lasts for 24 hours. The severity of the effect correlates with the dose and plasma concentration.

Pharmacokinetics

After oral administration, Felodipine is almost completely absorbed from the gastrointestinal tract. C_max is reached in 3-5 hours. Plasma protein binding (mainly to albumin) is about 99%. It penetrates the blood-brain barrier and placental barrier in small amounts and is excreted in breast milk. Felodipine is intensively metabolized in the liver; all its known metabolites are pharmacologically inactive. Metabolism occurs with the participation of isoenzymes CYP3A4, CYP3A5, CYP3A7.

About 70% is excreted by the kidneys as metabolites and less than 0.5% unchanged; the remainder is excreted through the intestines. T_1/2 in the α-phase is about 4 hours, in the β-phase – about 24 hours.

Indications

Arterial hypertension (as monotherapy or in combination with other antihypertensive drugs, such as beta-blockers, diuretics, or ACE inhibitors); stable angina pectoris (as monotherapy or in combination with beta-blockers).

ICD codes

Dosage Regimen

Administer orally once daily.

Swallow the extended-release tablet whole; do not crush, chew, or split.

Take the tablet in the morning, with a glass of water.

Initiate therapy with a 2.5 mg dose for most patients.

Increase the dose only after at least two weeks of treatment to achieve the desired therapeutic effect.

The usual maintenance dose is 5 mg or 10 mg once daily.

Do not exceed the maximum daily dose of 10 mg.

For elderly patients or those with hepatic impairment, initiate therapy with a 2.5 mg dose.

Exercise caution during subsequent dose titration in these patient populations.

For patients with severe renal impairment (creatinine clearance less than 30 ml/min), use with caution.

The dosage regimen must be individualized based on the patient’s therapeutic response and tolerability.

Adverse Reactions

Endocrine system: very rarely – hyperglycemia

Nervous system: frequently – headache; infrequently – dizziness, paresthesia.

Cardiovascular system: frequently – facial flushing, “hot flashes”; infrequently – tachycardia, palpitations, pronounced decrease in blood pressure accompanied by tachycardia, which in sensitive patients may cause or increase the frequency of angina attacks; rarely – syncope; very rarely – extrasystole

Digestive system: infrequently – nausea, abdominal pain; rarely – vomiting; very rarely – hyperplasia of the tongue and gum mucosa, gingivitis

Hepatobiliary system: very rarely – increased activity of liver enzymes in blood serum.

Skin and subcutaneous tissue disorders: infrequently – exanthema, skin itching; rarely – urticaria; very rarely – increased photosensitivity, leukocytoclastic vasculitis.

Musculoskeletal system: rarely – arthralgia, myalgia.

Other: very frequently – peripheral edema; infrequently – feeling of tiredness; rarely – impotence/sexual dysfunction; very rarely – frequent urination, hypersensitivity reactions (e.g., angioedema such as swelling of the lips or tongue, fever).

Contraindications

Hypersensitivity to felodipine; decompensated heart failure; acute myocardial infarction; unstable angina; hemodynamically significant heart valve stenosis; dynamic outflow tract obstruction of the heart; children and adolescents under 18 years of age; pregnancy; breastfeeding period.

With caution

Aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, labile blood pressure, impaired liver function, severe renal failure (creatinine clearance less than 30 ml/min), heart failure after acute myocardial infarction, elderly age, simultaneous use with inhibitors or inducers of the CYP3A4 isoenzyme. Arterial hypotension, which in predisposed patients may cause myocardial ischemia.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding). If use during lactation is necessary, the issue of discontinuing breastfeeding should be considered.

Use in Hepatic Impairment

Should be used with caution in patients with impaired liver function.

Use in Renal Impairment

Should be used with caution in patients with severe renal failure (creatinine clearance less than 30 ml/min).

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Should be used with caution in elderly patients.

Special Precautions

Felodipine may cause significant arterial hypotension with subsequent development of tachycardia. This may lead to the development of myocardial ischemia in predisposed patients with severe coronary artery disease.

Felodipine is metabolized in the liver. Therefore, in patients with impaired liver function, higher therapeutic concentrations of felodipine and response to treatment can be expected.

Concomitant use of felodipine with grapefruit juice should be avoided due to a significant increase in the plasma concentration of felodipine.

There are reports of cases of tongue and gum mucosal hyperplasia during the use of felodipine in patients with severe gingivitis/periodontitis. To avoid this side effect or reduce its manifestation, thorough oral hygiene should be maintained.

Effect on the ability to drive vehicles and operate machinery

During the use of felodipine, patients should exercise caution when driving vehicles and operating machinery, as well as when engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. At the beginning of therapy or during dose increase, patients should refrain from the above activities.

Drug Interactions

Felodipine is a substrate of the CYP3A4 isoenzyme of the cytochrome P450 system. Drugs that induce or inhibit the CYP3A4 isoenzyme have a significant effect on the plasma concentration of felodipine.

Drugs that induce the cytochrome P450 system (phenytoin, carbamazepine, phenobarbital, rifampicin, St. John’s wort tincture) enhance the metabolism of felodipine due to induction of the cytochrome P450 system.

Concomitant use of phenytoin, carbamazepine, phenobarbital, and rifampicin leads to a decrease in AUC values by 93% and C_max of felodipine by 82%. Concomitant use with inducers of the CYP3A4 isoenzyme should be avoided.

Drugs that inhibit the cytochrome P450 system – antifungal drugs of the triazole and imidazole derivatives (itraconazole, ketoconazole), macrolide antibiotics (e.g., erythromycin, clarithromycin), HIV protease inhibitors are inhibitors of the CYP3A4 isoenzyme.

When co-administered with itraconazole, the C_max of felodipine increases 8 times, AUC 6 times.

When co-administered with erythromycin, the C_max and AUC of felodipine increase approximately 2.5 times.

Grapefruit juice inhibits the CYP3A4 isoenzyme. Use of felodipine with grapefruit juice increases the C_max and AUC of felodipine approximately 2 times.

When used concomitantly, Felodipine may cause an increase in the plasma concentration of tacrolimus. Monitoring of tacrolimus serum concentration is recommended when using this combination.

When cyclosporine and felodipine are used concomitantly, the C_max of felodipine increases by 150%, AUC increases by 60%. The effect of felodipine on the pharmacokinetic parameters of cyclosporine is minimal.

Concomitant use of cimetidine and felodipine leads to an increase in the C_max and AUC of felodipine by 55%.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.