Aladin®-farmak

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALADIN®-FARMAK (ALADIN®-FARMAK)

Composition:

Active substance: amlodipine besylate;

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

Excipients: microcrystalline cellulose, anhydrous calcium hydrogen phosphate, sodium starch glycolate (type A), magnesium 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 vascular effect. 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 vascular smooth muscle cells.

The antihypertensive effect of amlodipine is due to its direct vasodilatory action on smooth muscle of blood vessels. 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). Since heart rate remains stable, this reduction in cardiac workload leads to decreased myocardial energy consumption and reduced myocardial 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 of 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 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. Absolute bioavailability of the unchanged molecule is approximately 64–80%. Peak plasma concentration (Cmax) 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. 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 concentration is achieved after 7–8 days of continuous drug 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 plasma concentrations of amlodipine is similar in elderly and adult patients. Amlodipine clearance is generally slightly reduced, leading to 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 amlodipine use 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. Oral clearance in children aged 6 to 12 years and 13 to 17 years was typically 22.5 L/h and 27.4 L/h, respectively, in boys, and 16.4 L/h and 21.3 L/h, 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 to 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, 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).

Cytochrome P450 (CYP3A4) inhibitors

Concomitant use of amlodipine with 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 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.

Cytochrome P450 (CYP3A4) inducers

Plasma concentrations of amlodipine may change following concomitant use with known CYP3A4 inducers. Therefore, blood pressure should be monitored and the dose adjusted accordingly during and after concomitant therapy, especially 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, 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 potentiate 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, should be performed in patients receiving both amlodipine and tacrolimus.

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

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, and cyclosporine dosage reduced 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 taking 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 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

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 with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Patients with hepatic impairment

The elimination half-life and AUC parameters of amlodipine are higher in patients with hepatic dysfunction; however, no specific dosage recommendations are available. Therefore, treatment in these patients should be initiated at the lowest dose. Caution is required both when starting treatment 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 group should be performed with caution.

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 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.

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

Fertility

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

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.

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

Lactation period

Amlodipine has been detected in breastfed infants whose mothers were taking amlodipine. 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 carefully weighed.

Ability to affect reaction speed when driving or operating machinery

The medicinal product Aladin®-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 Aladin®-Pharmak is 5 mg once daily. Depending on the patient's response to therapy, the dose may be increased to the maximum dose of 10 mg once daily.

Aladin®-Pharmak 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 ACE inhibitors in patients with arterial hypertension.

There is no need for dose adjustment when Aladin®-Pharmak 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 Aladin®-Pharmak for this patient group is 2.5 mg once daily (use amlodipine formulations with appropriate dosing). 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 cautiously.

Patients with renal impairment. 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 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 sections "Pharmacological properties. Pharmacokinetics" and "Special instructions").

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 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 a significant overdose of Aladin®-Pharmak will lead to excessive peripheral vasodilation and possibly reflex tachycardia. Cases of severe 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 arterial hypotension caused by amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory functions, elevation of the limbs, and monitoring of circulating fluid volume and urine output.

Vasoconstrictor 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 amlodipine significantly reduced its absorption.

Since amlodipine is highly protein-bound, dialysis is unlikely to be effective.

Adverse reactions.

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

Adverse reactions reported during amlodipine use 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), frequency 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.

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, gastrointestinal motility disturbances (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, Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, 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: 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 a study involving 268 children, the most frequently 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% of the placebo group. The most common reason for withdrawal from the study was uncontrolled arterial hypertension. No withdrawals were due to laboratory test abnormalities. No significant changes in pulse rate were observed.

Suspected adverse reactions reporting.

Reporting of suspected adverse reactions after medicinal product registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Do not use the medicinal product 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 of children.

Packaging. 10 tablets per blister. 2, 3, 5, 6, or 9 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.