Emlodine®

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

Composition:

Active substance: 1 tablet contains 2.5 mg or 5 mg or 10 mg of amlodipine (equivalent to
3.475 mg or 6.95 mg or 13.9 mg of amlodipine besylate, respectively);

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets 2.5 mg – white or almost white or yellowish-white, round, flat with a tablet bevel, engraved with a stylized letter E on one side and the number 251 on the other side, odorless or nearly odorless;

tablets 5 mg – white or almost white or yellowish-white, round, flat with a tablet bevel, engraved with a stylized letter E on one side and the number 252 on the other side, odorless or nearly odorless;

tablets 10 mg – white or almost white or yellowish-white, round, flat with a tablet bevel, engraved with a stylized letter E on one side and the number 253 on the other side, odorless or nearly odorless.

Pharmacotherapeutic group.
Selective calcium antagonists with predominant effect on blood vessels. 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 action of amlodipine is due to its direct vasodilating effect on vascular smooth muscle. The exact 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 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 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 in 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, once-daily dosing increases total exercise time, time to onset of angina, and time to 1 mm ST-segment depression. The drug reduces the frequency of anginal 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, and gout.

Pharmacokinetics.

Absorption/Distribution.

After oral administration of therapeutic doses, amlodipine is gradually absorbed into the 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. In vitro studies have shown that amlodipine binding to plasma proteins is approximately 97.5%.

Concomitant food intake does not affect amlodipine absorption.

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.

The time to reach steady-state plasma concentrations of amlodipine is similar in elderly and adult patients. Amlodipine clearance is generally slightly reduced in the elderly, resulting in increased area under the 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 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 liver dysfunction, amlodipine clearance is reduced, leading to prolonged elimination half-life and an increase in AUC by approximately 40–60%.

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 drug.
• 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, 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).

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 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.

There is no data 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, 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 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 tacrolimus blood levels and dose adjustment, if necessary, are required when used concomitantly with amlodipine.

Cyclosporine.

Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other patient groups, except in kidney transplant patients, in whom variable increases in cyclosporine trough concentrations (on average by 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 taking amlodipine, the dose of simvastatin should be limited to 20 mg daily.

Clinical interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

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.

Emlopin® 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 dysfunction; however, dosage recommendations are not established. Therefore, treatment in these patients should be initiated at the lowest dose. Caution should be exercised 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 group. 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.

Grapefruit or grapefruit juice should not be consumed with amlodipine, as in some patients this may increase bioavailability, leading to an enhanced hypotensive effect.

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.

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

Breastfeeding period.

It is unknown whether amlodipine is excreted in human breast milk. When making a decision on continuing breastfeeding or using 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 slight or moderate effect 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.

Dosage and Administration.

Adults.

For the treatment of arterial hypertension and angina pectoris, the usual initial dose of Emldin® 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.

The drug may be used in patients with angina either 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 the use of 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 of Emldin® 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 plasma concentrations of amlodipine 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 dosing range (see sections "Special Warnings" 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 and gradually increased.

Tablets of 5 mg may be divided in half to obtain a 2.5 mg dose.

Children.

The drug 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 is limited.

Symptoms of overdose: available data suggest that significant overdose of Emldin® may lead to excessive peripheral vasodilation and possibly reflex tachycardia. Cases of severe and potentially prolonged systemic arterial hypotension have been reported, including shock with fatal outcome.

Treatment: clinically significant 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 urinary output.

Vasoconstrictors 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.

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, ankle swelling, edema, and fatigue.

The adverse reactions reported during amlodipine administration 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 (≥ 1/10000 to < 1/1000), very rare (≤ 1/10000).

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 disorders (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 often 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, exfoliative dermatitis, erythema multiforme, Quincke's edema, photosensitivity.

Musculoskeletal and connective tissue disorders

Common: ankle 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: 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 frequently reported adverse reactions 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 withdrawal from the study was due to laboratory 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 continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with national regulatory requirements.

Shelf life. 5 years.

Storage conditions. Store at temperatures not exceeding 25 °C, protected from light and out of reach of children.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

EGIS Pharmaceuticals PLC, Hungary.

Manufacturer's address. 1165 Budapest, Bokenyfoldi ut. 118-120, Hungary.