Aladin

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

Composition:

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

Excipients:
Tablets Aladin® 10 mg – lactose monohydrate, potato starch, crospovidone, copovidone, colloidal anhydrous silicon dioxide, magnesium stearate;

Tablets Aladin® 5 mg – lactose monohydrate, corn starch, sodium croscarmellose, povidone, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: Aladin® 10 mg – white or almost white tablets with a flat surface, with a score line and beveled edges; Aladin® 5 mg – round, biconvex tablets of white or almost white color. Marbling on the tablet surface is permissible.

Pharmacotherapeutic group.

Selective calcium antagonists with predominant vascular effect. Dihydropyridine derivatives.

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 mechanism of amlodipine is due to its direct relaxing effect on vascular smooth muscle. The exact mechanism of the antianginal effect of amlodipine is not fully understood, but the effects described below play a certain role.

Amlodipine dilates peripheral arterioles, thereby reducing peripheral resistance (afterload). Since heart rate remains stable, the reduced cardiac workload leads to decreased energy consumption and reduced myocardial oxygen demand.

Dilation of major coronary arteries and coronary arterioles (both normal and ischemic) may also contribute to the mechanism of action of amlodipine. 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 of blood pressure over 24 hours in both supine and standing positions. Due to the slow onset of action of amlodipine, acute arterial hypotension is usually not observed.

In patients with angina, once-daily dosing 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 plasma. 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. 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 to 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, 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 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 an increase in AUC by approximately 40–60%.

Children. Oral clearance in children aged 6 to 12 years and 13 to 17 years was typically 22.5 and 27.4 L/h, respectively, in boys, and 16.4 and 21.3 L/h, respectively, in girls. There is considerable inter-patient variability in exposure. 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 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 co-administration 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 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 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 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.

CYP3A4 inducers.

There is no information available on the effect of CYP3A4 inducers on amlodipine. Concomitant use of amlodipine with substances that are CYP3A4 inducers (e.g., rifampicin, St. John’s wort) may lead to decreased plasma concentrations of amlodipine; therefore, such combinations should be used with caution.

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, 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 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, 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. 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 populations, except in kidney transplant patients, in whom variable increases in cyclosporine trough concentrations (on average 0–40%) have been observed. For kidney transplant patients receiving amlodipine, monitoring of cyclosporine concentrations should be considered, and cyclosporine dosage reduction may be 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-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.

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 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 cardiovascular events and future mortality.

Patients with hepatic impairment.

The elimination half-life and AUC parameters of amlodipine are higher in patients with impaired liver function; 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.

Dosage escalation should be performed cautiously in this patient group.

Patients with renal impairment.

Standard doses of the drug are recommended for this patient population. Plasma concentrations of amlodipine 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 of sodium (less than 23 mg), i.e., essentially sodium-free.

The Aladin® preparation contains lactose; therefore, this product should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Fertility.

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

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 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 the drug.

Lactation period.

Amlodipine has been detected in infants who were breastfed while their mothers were taking the drug. The amount of the maternal dose received by the infant was estimated to average 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.

Ability to affect reaction speed when driving or operating machinery.

Aladin® 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® 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.

Aladin® 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 with the use of Aladin® 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 Aladin® 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 of Aladin® for this patient group is 2.5 mg once daily (administer amlodipine in appropriate dosage forms). 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 daily 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 insufficiency.
Dosage recommendations 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 "Special Warnings and Precautions for Use" and "Pharmacological Properties. Pharmacokinetics").

The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. In patients with severe hepatic impairment, treatment with amlodipine should be initiated at the lowest dose, with gradual dose escalation.

Children.
Aladin® is indicated for use in 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 Aladin® is limited.

Symptoms of overdose: Available data suggest that significant overdose of Aladin® may 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 supporting perfusion and cardiac output.

Treatment:
Clinically significant hypotension due to 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 urinary 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 within 2 hours after ingestion of 10 mg amlodipine significantly reduced its absorption in healthy volunteers.

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

Adverse reactions.

The most commonly reported adverse reactions with amlodipine are: somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, leg 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).

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: 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: angioedema, Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, Quincke's edema, photosensitivity.

Musculoskeletal and connective tissue disorders.

Common: leg swelling, muscle cramps.

Uncommon: arthralgia, myalgia, back pain.

Renal and urinary disorders.

Uncommon: micturition disorder, 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) were observed 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 suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product is authorized 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 applicable legislation.

Shelf life.

Aladin® 10 mg – 3 years. Aladin® 5 mg – 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 in a blister. 3 or 5 blisters in a carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's address.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.