Amlodipine

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMLIDIPINE (AMLODIPINE)

Composition:

Active substance: amlodipine;

One tablet contains amlodipine besylate, calculated as amlodipine – 5 mg;

Excipients: lactose monohydrate, potato starch, povidone, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets with a flat surface, with a score line and bevel.

Pharmacotherapeutic group. Selective calcium antagonists with predominant effect on blood vessels. Dihydropyridine derivatives. ATC code C08CA01.

Pharmacological Properties

Pharmacodynamics

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

The antihypertensive effect of amlodipine is due to direct vasodilatory action on vascular smooth muscle. The precise mechanism of amlodipine's antianginal effect is not fully understood, but the following effects are believed to contribute:

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 reduced myocardial 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 the slow onset of amlodipine's action, 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 development of 1 mm ST-segment depression on ECG. 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 systemic circulation. 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 protein binding in plasma 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 administration. Amlodipine is primarily metabolized to 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 concentrations of amlodipine in plasma 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 metabolized to 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

Data on amlodipine use in patients with hepatic impairment are 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 of amlodipine 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 doses. Typical oral clearance values in children aged 6 to 12 years and 13 to 17 years were 22.5 and 27.4 L/hour, respectively, in boys, and 16.4 and 21.3 L/hour, respectively, in girls. There is considerable interpatient 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 interaction.

Effect of other medicinal products on amlodipine

Available safety data support the 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.

Data obtained 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 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, thereby 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 be altered when co-administered with CYP3A4 inducers. Therefore, blood pressure should be monitored and dosage adjusted accordingly, both during and after concomitant therapy, 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 have been observed after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, it is recommended to avoid the use of 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 potentiates the antihypertensive effects 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 tacrolimus blood levels and dose adjustment, if necessary, are required when used concomitantly with amlodipine.

Cyclosporine

No interaction studies between cyclosporine and amlodipine have been conducted in healthy volunteers or other patient groups, except in kidney transplant recipients, in whom variable increases in trough cyclosporine concentrations (on average by 0–40%) have been observed. In kidney transplant recipients receiving amlodipine, monitoring of cyclosporine concentrations should be considered, and cyclosporine dosage reduced if necessary.

mTOR inhibitors (mammalian target of rapamycin — target of rapamycin in mammals)

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.

Simvastatin

Concomitant administration of multiple doses of 10 mg amlodipine and 80 mg simvastatin 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 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.

Co-administration of amlodipine with aluminum/magnesium-containing antacids had no significant effect on amlodipine pharmacokinetics.

Ethanol (alcohol)

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

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 hepatic impairment; however, there are no specific dosage recommendations. Therefore, treatment in these patients should be initiated at the lowest dose. Caution should be exercised both when starting therapy and when increasing the dose. Patients with severe hepatic insufficiency may require slow dose titration and close monitoring.

Elderly patients.

Dosage increases in this patient group should be performed cautiously.

Patients with renal impairment.

Standard doses of the drug are recommended for this patient population. Changes in amlodipine plasma concentrations do not correlate with the degree of renal impairment. Amlodipine is not removed by dialysis.

Amlodipine does not interfere with laboratory test results.

The concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients this may increase bioavailability, leading to an enhanced hypotensive effect of the drug.

Patients with hereditary galactose intolerance, lactase deficiency, or glucose/galactose malabsorption syndrome should be aware that this medication contains lactose.

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 if no safer alternative is available 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.

Breastfeeding period.

Amlodipine is excreted in breast milk. The infant's exposure relative to the maternal dose is estimated to range between 3–7%, 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 the drug for the mother should be weighed.

Fertility.

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

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.

Amlodipine may be used in patients with angina either 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 of using 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 co-administering 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 for this patient group 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. The use of doses higher than 5 mg has not been studied in this patient group.

Elderly patients.

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

Patients with impaired renal function.

Standard doses 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 impaired hepatic function.

Doses for patients with mild to moderate hepatic impairment have not been established; therefore, dose titration should be performed with caution, and treatment should be initiated at the lowest dose within the dose range (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 and gradually increased.

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 data suggest 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.

Rarely, non-cardiogenic edema has been reported as a consequence of amlodipine overdose, which may manifest with delayed onset (24–48 hours after ingestion) and may require initiation of artificial ventilation. Early resuscitation measures (including fluid overload) to support perfusion and cardiac output may act as triggering 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 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 in 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.

Side effects

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

The side effects reported during amlodipine use 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), and not known (cannot be estimated from 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.

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 peristalsis 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.

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.

Rare cases of extrapyramidal syndrome have been reported.

Children

Amlodipine is well tolerated in children. The side effect profile is similar to that in adults. In a clinical study involving 268 children treated with amlodipine, the most commonly reported side effects were headache, dizziness, vasodilation, epistaxis, abdominal pain, and asthenia. Most adverse reactions were mild or moderate in severity. Serious 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 abnormalities. No significant changes in pulse rate were observed.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to 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 reach of children.

Packaging: 10 tablets in a blister. 3 blisters per carton.

Prescription status: Prescription only.

Manufacturer: JSC "Kyivmedpreparat".

Manufacturer's address and location of operations:

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.