Amlodipine 10

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMLODIPINE 5 AMLODIPINE 10 (AMLODIPINE 5 AMLODIPINE 10)

Composition:

active substance: amlodipine besylate;

1 tablet contains amlodipine besylate equivalent to 5 mg or 10 mg of amlodipine;

excipients: calcium hydrogen phosphate anhydrous, microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics:

tablets of 5 mg:

• tablets – straight, solid cylinders of white or almost white color, with flat end surfaces and a score line on one side;

tablets of 10 mg:

• tablets – straight, solid cylinders of white or almost white color, with flat end surfaces.

Pharmacotherapeutic group.

Selective calcium antagonists with predominant vascular effect. ATC code C08CA01.

Pharmacological properties.

Pharmacodynamics.

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

The antihypertensive effect of amlodipine is due to direct relaxation of 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.

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 expenditure 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 oxygenation 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 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, making it suitable for use in patients with asthma, diabetes mellitus, and gout.

Pharmacokinetics.

Absorption/Distribution

After oral administration of therapeutic doses, amlodipine is gradually absorbed into the plasma. Absolute bioavailability of the unchanged molecule is approximately 64–80%. Maximum plasma concentration (Cmax) is reached within 6–12 hours after drug administration. The volume of distribution is approximately 21 L/kg, and 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 younger adult patients. Amlodipine clearance is generally slightly reduced in the elderly, 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 concentration do not correlate with the degree of renal impairment. Standard doses of amlodipine can be used in patients with renal dysfunction. Amlodipine is not removed by dialysis.

Patients with hepatic impairment

Information regarding amlodipine use in patients with hepatic impairment is very limited. In patients with liver dysfunction, amlodipine clearance is reduced, resulting in 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 (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 divided 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. There is considerable inter-patient variability in exposure. Data in patients under 6 years of age are 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 interactions.

Effect of other medicinal products on amlodipine

Safety data are available for the use of amlodipine with thiazide diuretics, alpha-blockers, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, long-acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic agents.

Data from in vitro studies using human plasma 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 with 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, which could also increase the risk of hypotension. The clinical significance of such changes may be more pronounced in elderly patients. Clinical monitoring of the patient 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 following concomitant use with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dosage adjusted accordingly during and after concomitant therapy, particularly with strong CYP3A4 inducers (e.g., rifampicin, St. John's wort).

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, it is recommended to avoid using calcium channel blockers such as amlodipine 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 potentiate 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 understood. To avoid tacrolimus toxicity, regular monitoring of blood tacrolimus levels and, if necessary, dose adjustment of tacrolimus should be performed in patients receiving concomitant 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. Concomitant use of amlodipine with mTOR inhibitors may enhance the effects of the latter.

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%) were 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 antihypertensive 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 compared to 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 increased in patients with impaired liver function; however, specific dosage recommendations are not available. Therefore, treatment in these patients 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 escalation in this patient group should be performed cautiously.

Patients with renal impairment

Standard doses of the drug are recommended for 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.

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.

Sodium

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

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.

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 the risk associated with the underlying disease outweighs the potential risk to the mother and fetus.

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

Lactation 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 treatment for the mother should be carefully weighed.

Ability to affect reaction speed when driving or operating machinery.

Amlodipine may have a minor or moderate influence on the ability to drive or operate machinery.

Reaction speed may be reduced if symptoms such as dizziness, headache, confusion, or nausea occur.

Caution is advised, especially at the beginning of therapy.

Method of Administration and Dosage

Adults

For the treatment of arterial hypertension and angina pectoris, the usual initial dose of amlodipine is 5 mg 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 agents in cases of resistance to nitrates and/or adequate doses of beta-blockers.

There is experience with using the drug in combination with thiazide diuretics, alpha-blockers, beta-blockers, or ACE inhibitors in patients with arterial hypertension.

There is no need for dose adjustment when amlodipine is used concomitantly with thiazide diuretics, beta-blockers, or ACE inhibitors.

Children aged 6 years and older with arterial hypertension

The recommended initial dose of amlodipine 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

There is no need for dose adjustment in this patient group. Dose escalation should be performed cautiously.

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 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 within the recommended range (see sections "Pharmacological Properties. Pharmacokinetics" and "Special Warnings"). The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. In patients with severe hepatic impairment, amlodipine therapy should be initiated at the lowest dose and gradually increased.

Tablets of 5 mg may be split in half to achieve 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 overdose of the drug is limited.

Symptoms of overdose: available information suggests that significant overdose of amlodipine will lead to excessive peripheral vasodilation and possibly reflex tachycardia. Cases of marked and potentially prolonged systemic arterial hypotension have been reported, including shock with fatal outcome.

Rare cases of non-cardiogenic pulmonary edema have been reported as a consequence of amlodipine overdose, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Factors contributing 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 arterial hypotension caused by amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, elevation of the lower limbs, and monitoring of circulating fluid volume and urine output.

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

Since amlodipine is highly protein-bound, dialysis is of minimal benefit.

Adverse Reactions

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

Adverse reactions reported during treatment with amlodipine are listed below by system organ classes and frequency of occurrence: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (≤1/10,000), and frequency not known (cannot be estimated based on available data).

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.

Frequency 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: arterial hypotension.

Very rare: vasculitis.

Respiratory, thoracic and mediastinal disorders

Common: dyspnea.

Uncommon: cough, rhinitis.

Gastrointestinal disorders

Common: abdominal pain, nausea, dyspepsia, intestinal 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 commonly 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.

Frequency 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: increase or decrease in body weight.

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, nosebleeds, 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% of patients 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 suspected adverse reactions

Reporting 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 applicable legal requirements.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep out of reach and sight of children.

Packaging.

10 tablets per blister, 3, 6, or 9 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

JSC "Tekhnolohiya".

Manufacturer's address and place of business.

8 Stara Prorynna Street, Uman, Cherkasy Region, 20300, Ukraine.