Amlodipine-pharmak

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMLODIPINE-FARMAK (AMLODIPINE-FARMAK)

Composition:

Active ingredient: 1 tablet contains amlodipine besylate 13.90 mg or 6.95 mg (equivalent to amlodipine 10 mg or 5 mg);

Excipients:
Tablets Amlodipine-Farmak 10 mg – lactose monohydrate, potato starch, crospovidone, copovidone, colloidal anhydrous silicon dioxide, magnesium stearate;

Tablets Amlodipine-Farmak 5 mg – lactose monohydrate, corn starch, sodium croscarmellose, povidone, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:
Amlodipine-Farmak 10 mg – white or almost white tablets with a flat surface, with a score line and bevel;
Amlodipine-Farmak 5 mg – white or almost white, round-shaped, biconvex tablets. Marbling on the tablet surface is permissible.

Pharmacotherapeutic group.
Selective calcium antagonists with predominant vascular action. Dihydropyridine derivatives. ATC code C08CA01.

Pharmacological properties.

Pharmacodynamics.

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

The antihypertensive mechanism of action of amlodipine is due to its direct vasodilatory effect on vascular smooth muscle. The exact mechanism of amlodipine's antianginal effect is not fully understood, but the effects described below play a certain role.

Amlodipine dilates peripheral arterioles, thereby reducing peripheral resistance (afterload). Since heart rate remains stable, reduced cardiac workload leads to decreased myocardial energy consumption and oxygen demand.

Dilation of major coronary arteries and coronary arterioles (both normal and ischemic) may also contribute to the mechanism of action of amlodipine. This dilation increases myocardial oxygenation in patients with coronary artery spasm (Prinzmetal’s angina or variant angina).

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

In patients with angina, administration of a single daily dose increases total exercise duration, 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. Protein binding of amlodipine to plasma proteins is approximately 97.5%.

Concomitant food intake does not affect the absorption of amlodipine.

Metabolism/excretion. The elimination half-life from plasma is approximately 35–50 hours. Steady-state plasma concentrations are 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. The time to reach steady-state concentrations of amlodipine in plasma is similar in elderly patients and in adult patients. Amlodipine clearance is generally slightly reduced, resulting in increased area under the concentration-time curve (AUC) and prolonged elimination half-life in elderly patients.

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 amlodipine can be used in patients with renal impairment. 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 hepatic insufficiency, amlodipine clearance is reduced, leading to prolonged elimination half-life and an increase in AUC by approximately 40–60%.

Children. 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. There is considerable variability in exposure among individual patients. Information regarding 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 concomitant use 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 studies using human plasma have shown that amlodipine does not affect the protein binding of tested medicinal products (digoxin, phenytoin, warfarin, or indomethacin).

CYP3A4 inhibitors.

Concomitant use of amlodipine and strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in amlodipine exposure, which may 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 increase, thereby enhancing its hypotensive effect.

CYP3A4 inducers.

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

Dantrolene (infusions).

In animal studies, ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalemia were observed after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and during treatment of malignant hyperthermia.

Effect of amlodipine on other medicinal products.

The antihypertensive effect of amlodipine may be potentiated by 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 tacrolimus blood levels is recommended in patients receiving concomitant amlodipine, with dose adjustment of tacrolimus as necessary.

mTOR inhibitors (mammalian target of rapamycin).

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When used concomitantly with mTOR inhibitors, amlodipine may enhance their effects.

Cyclosporine.

Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other patient groups, except in kidney transplant recipients, in whom variable increases in cyclosporine trough concentrations (on average 0–40%) were observed. For kidney transplant patients receiving amlodipine, monitoring of cyclosporine concentrations should be considered, with cyclosporine dose reduction as 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-dose administration of 100 mg sildenafil in patients with essential hypertension had no effect on 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 administration of amlodipine with cimetidine had no effect on the pharmacokinetics of amlodipine.

Concomitant administration 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.

Amlodipine should be used with caution in this patient population. In a long-term placebo-controlled study in patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher with amlodipine than with placebo. Calcium channel blockers, including amlodipine, should be used cautiously in patients with congestive heart failure, as they may increase the risk of cardiovascular events and future mortality.

Patients with hepatic impairment.

The elimination half-life and AUC parameters of amlodipine are higher in patients with impaired liver function; however, dosage recommendations are not established. Therefore, treatment in this patient group should be initiated at the lowest dose. Caution is advised both when starting treatment and when increasing the dose. Patients with severe hepatic impairment may require slow dose titration and close monitoring.

Elderly patients.

Dose escalation should be performed cautiously in this patient population.

Patients with renal impairment.

This medication should be administered at usual doses in these patients. Changes in plasma concentrations of amlodipine do not correlate with the degree of renal impairment. Amlodipine is not removed by dialysis.

Amlodipine does not affect laboratory test results.

The 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 of the drug.

Fertility.

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

This medicinal product contains less than 1 mmol of sodium (less than 23 mg), i.e., essentially sodium-free.

The medicinal product Amlodipine-Farmak contains lactose; therefore, patients with rare hereditary disorders of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

The safety of amlodipine use in pregnant women has not been established.

Amlodipine should be used during pregnancy only if safer alternatives are unavailable and if the risk associated with the underlying disease outweighs the potential risk to the mother and fetus.

Reproductive toxicity was observed in animal studies with high doses of amlodipine.

Lactation period.

Amlodipine has been detected in infants who were breastfed while their mothers were receiving this medicinal product. The fraction of the maternal dose received by the infant has been estimated to average 3–7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.

When deciding whether to continue breastfeeding or to use amlodipine, the benefits of breastfeeding for the child and the benefits of therapy for the mother should be weighed.

Ability to affect reaction speed when driving or operating machinery.

Amlodipine-Farmak may have a minor or moderate influence on the ability to drive or operate machinery. Caution is advised, especially at the beginning of therapy.

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

Method of Administration and Dosage

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

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

There is experience with the use of the drug in combination with thiazide diuretics, alpha-blockers, beta-blockers, or angiotensin-converting enzyme inhibitors in patients with arterial hypertension.

There is no need for dose adjustment when the drug is used concomitantly with thiazide diuretics, beta-blockers, or angiotensin-converting enzyme inhibitors.

Children aged 6 years and older with arterial hypertension. The recommended initial dose of Amlodipine-Pharmak for this patient group is 2.5 mg once daily (administered at the appropriate dosage). If the target blood pressure level is not achieved within 4 weeks, the dose may be increased to 5 mg daily. Use of the drug at doses higher than 5 mg has not been studied in this patient population.

Elderly patients. Dose adjustment is not required for this patient group. Dose escalation should be performed cautiously.

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

Patients with hepatic impairment. Doses of the drug for patients with mild to moderate hepatic impairment have not been established; therefore, dose titration should be performed cautiously, starting with the lowest dose (see section "Special Warnings" and "Pharmacological Properties. Pharmacokinetics").

The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. For patients with severe hepatic impairment, amlodipine therapy should be initiated at the lowest dose, with gradual dose escalation.

Children. The drug is indicated for use 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 of the drug is limited.

Symptoms of overdose: Available data suggest that a significant overdose of Amlodipine-Pharmak will lead to excessive peripheral vasodilation and possibly reflex tachycardia. Cases of profound and potentially prolonged systemic hypotension have been reported, including shock with fatal outcome.

Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Contributing factors to the development of non-cardiogenic pulmonary edema may include early resuscitation measures (including fluid overload) aimed at maintaining perfusion and cardiac output.

Treatment: Clinically significant hypotension due to amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, elevation of the limbs, and monitoring of circulating fluid volume and urine output.

Vasoconstrictors 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 after ingestion of 10 mg amlodipine significantly reduced its absorption.

Since amlodipine is highly protein-bound, dialysis is expected to have minimal effect.

Adverse reactions.

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

Adverse reactions reported during the use of amlodipine are listed below by system organ classes and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (≤ 1/10,000).

Blood and lymphatic system disorders.

Very rare: leukopenia, thrombocytopenia.

Immune system disorders.

Very rare: allergic reactions.

Metabolism and nutrition disorders.

Very rare: hyperglycemia.

Psychiatric disorders.

Uncommon: depression, mood changes (including anxiety), insomnia.

Rare: confusion.

Nervous system disorders.

Common: somnolence, dizziness, headache (mainly at the beginning of treatment).

Uncommon: tremor, dysgeusia, syncope, hypesthesia, paresthesia.

Very rare: hypertonia, peripheral neuropathy.

Eye disorders.

Common: visual disturbances (including diplopia).

Ear and labyrinth disorders.

Uncommon: tinnitus.

Cardiac disorders.

Common: palpitations.

Uncommon: arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation).

Very rare: myocardial infarction.

Vascular disorders.

Common: flushing.

Uncommon: hypotension.

Very rare: vasculitis.

Respiratory, thoracic and mediastinal disorders.

Common: dyspnea.

Uncommon: cough, rhinitis.

Gastrointestinal disorders.

Common: abdominal pain, nausea, dyspepsia, gastrointestinal motility disorders (including diarrhea and constipation).

Uncommon: vomiting, dry mouth.

Very rare: pancreatitis, gastritis, gingival hyperplasia.

Hepatobiliary disorders.

Very rare: hepatitis, jaundice, increased liver enzymes (most often associated with cholestasis).

Skin and subcutaneous tissue disorders.

Uncommon: alopecia, purpura, skin discoloration, increased sweating, pruritus, rash, exanthema, urticaria.

Very rare: angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity.

Musculoskeletal and connective tissue disorders.

Common: leg swelling, muscle cramps.

Uncommon: arthralgia, myalgia, back pain.

Renal and urinary disorders.

Uncommon: urinary disorders, nocturia, increased frequency of urination.

Reproductive system and breast disorders.

Uncommon: impotence, gynecomastia.

General disorders and administration site conditions.

Very common: edema.

Common: fatigue, asthenia.

Uncommon: chest pain, pain, malaise.

Investigations.

Uncommon: weight gain or weight loss.

Rare cases of extrapyramidal syndrome have been reported.

Children.

Amlodipine is well tolerated in children. The adverse reaction profile was similar to that observed in adults. In a study involving 268 children, the most commonly reported adverse reactions were: headache, dizziness, vasodilation, epistaxis, abdominal pain, and asthenia.

Most adverse reactions were mild or moderate in severity. Severe adverse reactions (mainly headache) occurred in 7.2% of patients receiving 2.5 mg amlodipine, in 4.5% receiving 5 mg amlodipine, and in 4.6% in the placebo group. The most common reason for withdrawal from the study was uncontrolled hypertension. No withdrawals were due to laboratory test abnormalities. No clinically significant changes in pulse rate were observed.

Reporting of suspected adverse reactions.

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

Shelf life.

3 years.

Do not use the medicine after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach and sight of children.

Packaging.

10 tablets in a blister. 1 or 2 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's name and address.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.