Amlodipine-zdorovya

INSTRUCTIONS FOR MEDICAL USE of the medicinal product AMLODIPINE-ZDOROVIYA

Composition:

Active substance: 1 tablet contains amlodipine besylate equivalent to amlodipine 5 mg or 10 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, monohydrate lactose, calcium hydrogen phosphate anhydrous, colloidal silicon dioxide anhydrous, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: 5 mg tablets are white or white with a creamy shade, flat cylindrical in shape with a bevel;

10 mg tablets are white or white with a creamy shade, flat cylindrical in shape with a score line and a bevel.

Pharmacotherapeutic group. Selective calcium antagonists with predominant effect on blood vessels.

ATC code C08CA01.

Pharmacological properties.

Pharmacodynamics. Amlodipine is a calcium antagonist (a dihydropyridine derivative) that blocks the influx of calcium ions into myocardial and smooth muscle cells.

The antihypertensive mechanism of action of amlodipine is due to its direct relaxing effect on vascular smooth muscle. The exact mechanism of amlodipine's antianginal effect is not fully understood, but the following effects are believed to play a role.

1. Amlodipine dilates peripheral arterioles, thereby reducing peripheral resistance (afterload). Since heart rate remains stable, this reduction in cardiac workload leads to decreased myocardial energy consumption and oxygen demand.
2. Dilation of major coronary arteries and coronary arterioles (both normal and ischemic) may also contribute to amlodipine's mechanism of action. This dilation increases myocardial oxygen supply in patients with coronary artery spasm (Prinzmetal’s angina or variant angina).

In patients with arterial hypertension, once-daily administration of the drug provides clinically significant reduction in arterial blood pressure over 24 hours, both in supine and standing positions. Due to amlodipine’s slow onset of action, acute arterial hypotension is usually not observed.

In patients with angina, administration of a single daily dose increases total exercise time, time to onset of angina, and time to 1 mm ST-segment depression. The drug reduces the frequency of angina attacks and decreases the need for nitroglycerin use.

Amlodipine is not associated with any adverse metabolic effects or changes in plasma lipid levels and can be used in patients with asthma, diabetes mellitus, and gout.

Pharmacokinetics.

Absorption/distribution. After oral administration of therapeutic doses, amlodipine is gradually absorbed into plasma. The absolute bioavailability of the unchanged molecule is approximately 64–80%. Peak plasma concentration is reached within 6–12 hours after administration. The volume of distribution is approximately 21 L/kg; the acid dissociation constant (pKa) of amlodipine is 8.6. In vitro studies have shown that amlodipine binding to plasma proteins is approximately 97.5%.

Concomitant food intake does not affect amlodipine absorption.

Metabolism/elimination. The elimination half-life from plasma is approximately 35–50 hours. Steady-state plasma concentration is achieved after 7–8 days of continuous drug administration. Amlodipine is primarily metabolized into inactive metabolites. Approximately 60% of the administered dose is excreted in urine, of which about 10% is unchanged amlodipine.

Elderly patients. Time to reach steady-state plasma concentrations of amlodipine is similar in elderly and adult patients. Amlodipine clearance is generally slightly reduced in elderly patients, resulting in increased area under the concentration-time curve (AUC) and prolonged elimination half-life.

Patients with renal impairment. Amlodipine is extensively biotransformed into inactive metabolites. About 10% of amlodipine is excreted unchanged in urine. Changes in amlodipine plasma concentrations do not correlate with the degree of renal impairment. Standard doses of amlododipine can be used in patients with impaired renal function. Amlodipine is not removed by dialysis.

Patients with hepatic impairment. Information on the use of amlodipine in patients with hepatic impairment is very limited. In patients with liver insufficiency, amlodipine clearance is reduced, leading to prolonged elimination half-life and an increase in AUC by approximately 40–60%.

Children. Pharmacokinetic studies were conducted in 74 children aged 12 to 17 years with arterial hypertension (including 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) who received amlodipine at doses of 1.25–20 mg daily in one or two doses. Oral clearance in children aged 6 to 12 years and 13 to 17 years was typically 22.5 and 27.4 L/hour, respectively, in boys, and 16.4 and 21.3 L/hour, respectively, in girls. Considerable interpatient variability in exposure was observed. Information in patients under 6 years of age is limited.

Clinical characteristics.

Indications.

• Arterial hypertension.
• Chronic stable angina.
• Vasospastic angina (Prinzmetal's angina).

Contraindications.

• Known hypersensitivity to dihydropyridines, amlodipine, or any other component of the medicinal product.

• Severe arterial hypotension.

• Shock (including cardiogenic shock).

• Left ventricular outflow tract obstruction (e.g., severe aortic stenosis).

• Hemodynamically unstable heart failure following acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on amlodipine.

Available data indicate safe co-administration of amlodipine with thiazide diuretics, alpha-blockers, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic agents.

In vitro, amlodipine has no effect on the protein binding of medicinal products such as digoxin, phenytoin, warfarin, or indomethacin.

Effect of other medicinal products on amlodipine.

CYP3A4 inhibitors. Concomitant use of amlodipine with strong or moderately potent CYP3A4 inhibitors (protease inhibitors, azole antifungal agents, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in amlodipine exposure, which could also increase the risk of hypotension. The clinical significance of such changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may be necessary.

Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients the bioavailability of amlodipine may be increased, thereby enhancing its hypotensive effect.

CYP3A4 inducers. There is no information on the effect of CYP3A4 inducers on amlodipine. Concomitant use of amlodipine with substances that are CYP3A4 inducers (e.g., rifampicin, St. John's wort) may lead to decreased plasma concentrations of amlodipine; therefore, such combinations should be used with caution.

Dantrolene (infusions). Ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalemia have been observed in animals following intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, the use of calcium channel blockers such as amlodipine is recommended to be avoided in patients susceptible to malignant hyperthermia and in the treatment of malignant hyperthermia.

Effect of amlodipine on other medicinal products.

The antihypertensive effect of amlodipine potentiates the antihypertensive effect of other antihypertensive agents.

Tacrolimus. There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine, although the pharmacokinetic mechanism of this interaction is not fully established. To avoid tacrolimus toxicity, regular monitoring of blood tacrolimus levels and, if necessary, dose adjustment should be performed in patients receiving amlodipine.

Cyclosporine. Studies on interactions between cyclosporine and amlodipine have not been conducted in healthy volunteers or other groups, except in kidney transplant patients, in whom variable increases in cyclosporine trough concentrations (on average 0–40%) have been observed. For kidney transplant patients receiving amlodipine, monitoring of cyclosporine concentrations should be considered, and cyclosporine dosage reduced if necessary.

Simvastatin. Concomitant administration of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. In patients receiving amlodipine, the dose of simvastatin should be limited to 20 mg daily.

Sildenafil.

Single administration of 100 mg sildenafil in patients with essential hypertension did not affect the pharmacokinetics of amlodipine. When amlodipine and sildenafil are used concomitantly as combination therapy, each drug exerts its hypotensive effect independently of the other.

Other medicinal products.

Clinical interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

Ethanol (alcohol).

Single and multiple doses of 10 mg amlodipine had no significant effect on the pharmacokinetics of ethanol.

Concomitant use of amlodipine with cimetidine had no effect on the pharmacokinetics of amlodipine.

Concomitant use of aluminum/magnesium-containing products (antacids) with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

Laboratory tests.

The effect on laboratory test parameters is unknown.

Special precautions for use. The safety and efficacy of amlodipine in hypertensive crisis have not been evaluated.

Patients with heart failure.

This category of patients should be treated with caution. Data indicate that in patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher with amlodipine compared to patients not receiving amlodipine. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of cardiovascular events and mortality in the future.

Patients with hepatic impairment.

The elimination half-life and AUC parameters of amlodipine are higher in patients with hepatic impairment; dosage recommendations are not available. Therefore, treatment in this patient group should be initiated at the lowest dose. Caution is required both at the start of treatment and during dose escalation. Patients with severe hepatic impairment may require slow dose titration and careful monitoring.

Elderly patients.

Dose adjustment is not required in this patient group. Dose increases should be performed cautiously.

Patients with renal impairment.

Standard doses of the medicinal product are recommended, as changes in plasma concentrations of amlodipine do not correlate with the degree of renal dysfunction. Amlodipine is not removed by dialysis.

Amlodipine does not affect the results of laboratory tests.

Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients bioavailability may be increased, leading to an enhanced hypotensive effect.

Fertility.

Reversible biochemical changes in the sperm head have been reported in some patients receiving calcium channel blockers. Clinical information on the potential effect of amlodipine on fertility is insufficient.

The medicinal product contains lactose; therefore, if the patient has been diagnosed with intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Use in pregnancy or breastfeeding. The safety of amlodipine use in pregnant women has not been established.

Amlodipine should be used during pregnancy only when safer alternatives are unavailable and when the risk associated with the disease itself outweighs the potential harm of treatment to the mother and fetus.

In animal studies, reproductive toxicity was observed with high doses.

Breastfeeding period. It is unknown whether amlodipine passes into breast milk. When deciding whether to continue breastfeeding or to use amlodipine, the benefit of breastfeeding for the child and the benefit of treatment for the mother should be weighed.

Ability to affect reaction speed when driving or operating machinery. Amlodipine may have a negligible or moderate effect on the ability to drive or operate machinery.

Reaction speed may be reduced in the presence of symptoms such as dizziness, headache, confusion, or nausea.

Caution is advised, especially at the beginning of therapy.

Method of administration and dosage.

Adults.

For the treatment of arterial hypertension and angina, the usual initial dose is 5 mg once daily. Depending on the patient's response to therapy, the dose may be increased up to a maximum of 10 mg once daily.

In patients with angina, the medicinal product may be used as monotherapy or in combination with other antianginal agents in cases of resistance to nitrates and/or adequate doses of beta-blockers.

Experience exists with the use of the medicinal product in combination with thiazide diuretics, alpha-blockers, beta-blockers, or angiotensin-converting enzyme inhibitors in patients with arterial hypertension.

Dose adjustment is not required when amlodipine is used concomitantly with thiazide diuretics, beta-blockers, or angiotensin-converting enzyme inhibitors.

For children aged 6 years and older with arterial hypertension, the recommended initial dose is 2.5 mg once daily. If the desired blood pressure level is not achieved within 4 weeks, the dose may be increased to 5 mg daily. Data on the use of doses higher than 5 mg in this patient group are lacking.

Elderly patients.

Dose adjustment is not required for this patient group. Dose increases should be performed cautiously.

Patients with renal impairment.

Standard doses are recommended, as changes in plasma concentrations of amlodipine are not related to the severity of renal impairment. Amlodipine is not eliminated by dialysis.

Patients with hepatic impairment.

Dosage recommendations for patients with mild to moderate hepatic impairment have not been established; therefore, dose titration should be performed cautiously, and treatment should be initiated at the lowest dose within the dosing range (see sections "Special precautions for use" and "Pharmacological properties. Pharmacokinetics"). The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. In patients with severe hepatic impairment, treatment with amlodipine should be initiated at the lowest dose and gradually increased.

Tablets containing 5 mg of the active substance are not intended to be split to obtain a 2.5 mg dose; therefore, amlodipine at a dose of 2.5 mg should be prescribed in medicinal forms with appropriate dosage strengths.

Children. The medicinal product may be used in children aged 6 years and older. The effect of amlodipine on blood pressure in patients under 6 years of age is unknown.

Overdose. Experience with intentional overdose is limited.

Symptoms of overdose: significant overdose leads to excessive peripheral vasodilation and possibly reflex tachycardia. Severe and potentially prolonged systemic arterial hypotension, including shock with fatal outcome, has been reported.

Rarely, non-cardiogenic pulmonary edema has been reported following amlodipine overdose, which may have a delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Early resuscitative measures (including fluid loading) to support perfusion and cardiac output may be precipitating factors.

Treatment: clinically significant arterial hypotension caused by amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, elevation of the lower extremities, and monitoring of circulating fluid volume and urine output.

Vasoconstrictor agents may be used to restore vascular tone and blood pressure, provided there are no contraindications to their use. Intravenous calcium gluconate may be beneficial in counteracting the effects of calcium channel blockade.

In some cases, gastric lavage may be helpful. Administration of activated charcoal to healthy volunteers within 2 hours of 10 mg amlodipine intake significantly reduced its absorption.

Due to the high degree of protein binding of amlodipine, dialysis is of minimal benefit.

Adverse reactions.

The most commonly reported adverse reactions with amlodipine are: somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, leg swelling, edema, and fatigue.

Blood and lymphatic system disorders: leukopenia, thrombocytopenia.

Immune system disorders: allergic reactions.

Metabolism and nutrition disorders: hyperglycemia.

Psychiatric disorders: depression, mood changes (including anxiety), insomnia, confusion.

Nervous system disorders: somnolence, dizziness, headache (mainly at the beginning of treatment), tremor, dysgeusia, syncope, hypesthesia, paresthesia, hypertonia, peripheral neuropathy.

Eye disorders: visual disturbances (including diplopia).

Ear and labyrinth disorders: tinnitus.

Cardiac disorders: palpitations, arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation), myocardial infarction.

Vascular disorders: flushing, hypotension, vasculitis.

Respiratory, thoracic and mediastinal disorders: dyspnea, cough, rhinitis.

Gastrointestinal disorders: abdominal pain, nausea, dyspepsia, gastrointestinal motility disorders (including diarrhea and constipation), vomiting, dry mouth, pancreatitis, gastritis, gingival hyperplasia.

Hepatobiliary disorders: hepatitis, jaundice, increased levels of liver enzymes (most commonly associated with cholestasis).

Skin and subcutaneous tissue disorders: alopecia, purpura, skin discoloration, increased sweating, pruritus, rash, exanthema, urticaria, angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity.

Musculoskeletal and connective tissue disorders: leg swelling, muscle cramps, arthralgia, myalgia, back pain.

Renal and urinary disorders: urinary disorders, nocturia, increased frequency of urination.

Reproductive system and breast disorders: impotence, gynecomastia.

General disorders and administration site conditions: edema, fatigue, asthenia, chest pain, pain, malaise.

Investigations: increased or decreased body weight.

Rare cases of extrapyramidal syndrome have been reported.

Children.

Amlodipine is well tolerated in pediatric patients. The adverse reaction profile is similar to that observed in adults. The most commonly observed adverse reactions in children are: headache, dizziness, vasodilation, epistaxis, abdominal pain, asthenia, uncontrolled hypertension.

Most adverse reactions were mild or moderate in severity.

Reporting of suspected adverse reactions. Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with national regulatory requirements.

Shelf life. 5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. Tablets of 5 mg or 10 mg, 10×3 in blisters in a carton.

Prescription status. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and place of business. Ukraine, 61013, Kharkiv region, Kharkiv, Shevchenka Street, 22.