Amlodipine-astrafarm

INSTRUCTIONS FOR MEDICINAL USE OF THE MEDICINAL PRODUCT AMLODIPINE-ASTRAPHARM (AMLODIPINE-ASTRAPHARM)

Composition:

Active substance: amlodipine;

1 tablet contains amlodipine besylate, equivalent to 100% substance 5 mg or 10 mg;

Excipients: calcium hydrogen phosphate, microcrystalline cellulose, magnesium stearate, maize starch.

Pharmaceutical form. Tablets.

Main physicochemical properties: white-colored tablets, flat cylindrical shape, beveled edges, with a score line on one side.

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics.

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

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

• Amlodipine dilates peripheral arterioles, thereby reducing peripheral resistance (afterload). This reduction in 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 amlodipine’s mechanism of action. This vasodilation 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 the slow onset of amlodipine’s action, acute 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 the bloodstream. 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 plasma protein binding of amlodipine 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 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 plasma 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 amlodipine 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 dysfunction, 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 with arterial hypertension aged 12 to 17 years (also 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. Typical oral clearance values in children aged 6 to 12 years and 13 to 17 years were 22.5 and 27.4 L/h, respectively, in boys, and 16.4 and 21.3 L/h, respectively, in girls. There is considerable interpatient variability in exposure. Information regarding patients under 6 years of age is limited.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to dihydropyridines, amlodipine, or to any other component of the medicinal product.
• Severe arterial hypotension.
• Shock (including cardiogenic shock).
• Obstruction of the left ventricular outflow tract (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 support the safe use of amlodipine with thiazide diuretics, α-blockers, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, long-acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic agents.

Data obtained from in vitro human plasma studies indicate that amlodipine does not affect the protein binding of tested medicinal products (digoxin, phenytoin, warfarin, or indomethacin).

Inhibitors of CYP3A4.

Concomitant use of amlodipine and strong or moderate 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, increasing the risk of arterial 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.

Inducers of CYP3A4.

Plasma concentrations of amlodipine may change when co-administered with known CYP3A4 inducers. Therefore, monitoring of blood pressure and appropriate dose adjustment during and after concomitant therapy is advised, particularly with strong CYP3A4 inducers (e.g., rifampicin, St. John’s wort).

Dantrolene (infusions).

In animals, 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, the use of calcium channel blockers such as amlodipine is not recommended in patients susceptible to malignant hyperthermia or during treatment of malignant hyperthermia.

Effect of amlodipine on other medicinal products.

The antihypertensive effect of amlodipine potentiates the hypotensive 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 understood. To avoid tacrolimus toxicity, monitoring of blood tacrolimus levels and dose adjustment, if necessary, is required when used concomitantly with amlodipine.

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.

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 by 0–40%) were observed. In kidney transplant patients receiving amlodipine, monitoring of cyclosporine concentrations and, if necessary, dose reduction of cyclosporine are recommended.

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 taking amlodipine, the dose of simvastatin should be limited to 20 mg daily.

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

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 administration of amlodipine with cimetidine did not affect 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. This medicinal product should be used with caution in this patient group. Calcium channel blockers, including amlodipine, should be administered with caution to patients with congestive heart failure, as they may increase the risk of future cardiovascular complications and mortality. Clinical studies have shown that in patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher with amlodipine compared to placebo.

Patients with hepatic impairment. The elimination half-life and AUC parameters of amlodipine are increased in patients with impaired liver function; however, no specific dosage recommendations are available. Therefore, treatment in this patient group should be initiated at the lowest dose.

Caution should be exercised 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 escalation in this patient group should be performed with caution.

Patients with renal impairment. This medicinal product should be administered at the usual doses in this patient group. Changes in amlodipine plasma concentrations 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.

Sodium.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

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 underlying disease outweighs the potential harm of treatment to the mother and fetus.

Reproductive toxicity was observed in animal studies with high doses.

Breastfeeding period.

Amlodipine is excreted in breast milk. The infant dose received from the mother is estimated to be 3–7% of the maternal dose (interquartile range), with a maximum of 15%. The effects of amlodipine on infants are 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.

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.

Ability to affect reaction speed when driving or operating machinery.

Amlodipine may have a slight or moderate influence 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.

Dosage and Administration.

Adults.

For the treatment of arterial hypertension and angina, the recommended initial dose of the medicinal product is 5 mg of amlodipine once daily. Depending on the patient's response to therapy, the dose may be increased up to the 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 β-blockers.

There is experience with the use of the drug in combination with thiazide diuretics, α-blockers, β-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, β-blockers, or angiotensin-converting enzyme inhibitors.

Children aged 6 years and older with arterial hypertension.

The recommended initial dose for this patient group is 2.5 mg once daily. If the target blood pressure level is not achieved within 4 weeks, the dose may be increased to 5 mg daily. The use of doses higher than 5 mg in this patient group has not been studied.

Elderly patients.

Dose adjustment is not required for this patient group. Dose escalation should be performed with caution.

Patients with renal impairment.

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

Patients with hepatic impairment.

Doses for use in patients with mild to moderate hepatic impairment have not been established; therefore, dose titration should be performed cautiously, starting with the lowest dose (see sections "Special Warnings" and "Pharmacological Properties. Pharmacokinetics"). The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. In patients with severe hepatic dysfunction, amlodipine therapy should be initiated at the lowest dose with gradual dose escalation.

Tablets of 5 mg may be split in half to obtain a 2.5 mg dose.

Children.

The drug may be administered to 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 amlodipine overdose is limited.

Symptoms: significant overdose of the drug leads to excessive peripheral vasodilation and possibly reflex tachycardia. Cases of severe and prolonged systemic arterial hypotension have been reported, including fatal shock.

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. Early resuscitative measures (including fluid loading) to support perfusion and cardiac output may act as triggering factors.

Treatment: clinically significant hypotension caused by 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 urinary output.

Vasoconstrictor agents may be used to restore vascular tone and arterial 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 10 mg amlodipine intake 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 during amlodipine administration include: somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, leg swelling, edema, and fatigue.

Adverse reactions reported during amlodipine use are listed below by system organ class 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), and not known (cannot be estimated from available data).

Blood system disorders:

Very rare: leukopenia, thrombocytopenia.

Immune system disorders:

Very rare: allergic reactions.

Metabolic and nutritional disorders:

Very rare: hyperglycemia.

Psychiatric disorders:

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

Very 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.

Not known: extrapyramidal disorders.

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, altered bowel motility (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: angioneurotic edema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity.

Not known: toxic epidermal necrolysis.

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: increased fatigue, asthenia.

Uncommon: chest pain, pain, malaise.

Investigations:

Uncommon: weight gain or weight loss.

Rare cases of extrapyramidal syndrome development have been reported.

Children

Amlodipine is well tolerated in pediatric patients. The adverse reaction profile was similar to that observed in adults. In pediatric studies, 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% of patients 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 abnormalities. No significant changes in pulse rate were observed.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is extremely important. It allows continued 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. 3 years.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

10 tablets in a blister; 2, 3, 6, 9, or 10 blisters in a carton.

Prescription status. Prescription only.

Manufacturer.

LLC "Astafarm".

Manufacturer's address and place of business.

6 Kyivska Street, Vyshneve, Kyiv-Sviatoshyn District, Kyiv Oblast, 08132, Ukraine.