Amlodipine

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

Composition:

Active substance: amlodipine besylate;

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

Excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, hypromellose (hydroxypropylmethylcellulose), povidone 25, magnesium stearate, colloidal anhydrous silicon dioxide, indigocarmine (E 132).

Pharmaceutical form. Tablets.

Main physicochemical properties: single-layer, round-shaped tablets of white or white with a bluish tint color; the upper and lower surfaces are convex. When viewed under a magnifying glass, the cross-section reveals a relatively homogeneous structure.

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 cells and vascular smooth muscle cells.

The antihypertensive effect of amlodipine is due to its direct vasodilatory action 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:

1. Amlodipine dilates peripheral arterioles, thereby reducing peripheral resistance (afterload). This reduction in cardiac workload leads to decreased myocardial energy consumption and oxygen demand.
2. Dilation of major coronary arteries and coronary arterioles 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 of arterial blood pressure over 24 hours, both in supine and standing positions. Due to the slow onset of action of amlodipine, acute hypotension is usually not observed.

In patients with angina, administration of a single daily dose increases total exercise duration. 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. Concomitant food intake does not affect the absorption of amlodipine. 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%.

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 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 metabolized to inactive metabolites. About 10% of amlodipine is excreted unchanged in urine. Plasma amlodipine 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, resulting in prolonged elimination half-life and increased 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 once or twice daily. 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 inter-patient variability in exposure is 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 support the safe use of amlodipine with thiazide diuretics, alpha-blockers, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and oral hypoglycemic agents.

Data from in vitro studies using human plasma indicate no effect of amlodipine on 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 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 these 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.

Plasma concentrations of amlodipine may be altered when co-administered with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dosage adjusted accordingly during and after concomitant therapy, especially 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, calcium channel blockers such as amlodipine should 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 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 understood. To avoid tacrolimus toxicity during concomitant use with amlodipine, regular monitoring of tacrolimus blood levels is required, with dose adjustment if 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 by 0–40%) have been observed. In kidney transplant recipients receiving amlodipine, monitoring of cyclosporine concentrations should be considered, with cyclosporine dose reduction if necessary.

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 simvastatin dose should be limited to 20 mg daily.

Sildenafil.

Single 100 mg dose of 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.

Ethanol.

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

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 cimetidine had no effect on the pharmacokinetics of amlodipine.

Co-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 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 with caution 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 hepatic impairment; however, no specific dosage recommendations are available. 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 impairment may require slow dose titration and careful monitoring.

Elderly patients

Dose escalation in this patient population should be performed with caution.

Patients with renal impairment

The usual 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 affect 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.

Excipients

The medicinal product contains lactose. Patients with rare hereditary disorders such as 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 when safer alternatives are unavailable and when 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 passes into breast milk. The amount transferred to the infant 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 carefully weighed.

Fertility

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

Influence on ability to drive and use machines

Amlodipine may have a negligible or moderate influence on the ability to drive vehicles 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 pectoris, the usual initial dose of the drug is 5 mg once daily. Depending on the patient's response to therapy, the dose may be increased to a maximum dose of 10 mg once daily.

For 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 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 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 in this patient group has not been studied.

Elderly patients.

There is no need for dose adjustment in this patient group. Dose increases 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.

Dosage recommendations for patients with mild to moderate hepatic impairment have not been established; therefore, dose titration should be performed with caution, starting with the lowest dose within the recommended dose range (see sections "Special Instructions" and "Pharmacological Properties. Pharmacokinetics").

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 with gradual dose escalation.

Tablets containing 5 mg of the drug are not intended to be split 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: significant overdose of the drug leads 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. 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 arterial hypotension caused by amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, elevation of the lower limbs, monitoring of circulating fluid volume and urine output.

Vasoconstrictors may be used to restore vascular tone and arterial pressure, provided there are no contraindications to their use. Intravenous administration of 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 unlikely to be effective.

Side effects.

When amlodipine is used, the most commonly reported adverse reactions are: somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, edema, and increased fatigue.

Adverse reactions reported during the use of amlodipine are listed below by system organ classes and frequency of occurrence: 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), not known (cannot be estimated from the 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.

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 levels of 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: ankle 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 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 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 in the original packaging at a temperature not exceeding 30°C.

Keep out of reach and sight of children.

Packaging.

For 5 mg dosage:

10 tablets in a blister; 3, 6, or 9 blisters in a cardboard pack;

10 tablets in a blister; 100 blisters in a cardboard box.

For 10 mg dosage:

10 tablets in a blister; 3, 6, or 9 blisters in a cardboard pack;

10 tablets in a blister; 90 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

PJSC "Tekhnolohiya".

Manufacturer's address and location of its business activity.

8 Stara Prorizna Street, Uman, Cherkasy region, 20300, Ukraine.