Amlodipine euro

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

Composition:

Active substance: amlodipine;

1 5 mg tablet contains amlodipine besylate 6.935 mg equivalent to amlodipine 5 mg;

1 10 mg tablet contains amlodipine besylate 13.870 mg equivalent to amlodipine 10 mg;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: white to almost white, round, flat tablets with bevelled edges and a score line on one side.

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

• 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.
• 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 arterial blood pressure over 24 hours, in both supine and standing positions. Due to the slow onset of action of amlodipine, acute 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. It 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. In vitro studies have shown that plasma protein binding of amlodipine is approximately 97.5%.

Concomitant food intake does not affect the absorption of amlodipine.

Metabolism/elimination.

The elimination half-life from plasma is approximately 35–50 hours. Steady-state plasma concentrations are achieved after 7–8 days of continuous treatment. 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 usually 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 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.

Data on the use of amlodipine in patients with hepatic impairment are very limited. In patients with hepatic insufficiency, amlodipine clearance is reduced, leading to prolonged elimination half-life and an increase in AUC by approximately 40–60%.

Children.

Pharmacokinetic studies have been 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. These studies demonstrated that oral clearance in children aged 6 to 12 years and 13 to 17 years was generally 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 was observed. 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 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; pediatric age under 6 years.

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, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic agents.

In vitro data from human plasma studies 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 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.

Plasma concentrations of amlodipine may change when co-administered with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dose adjustments made accordingly, both during and after concomitant therapy, particularly with strong CYP3A4 inducers (e.g., rifampicin, St. John’s wort).

Dantrolene (infusions).

In animal studies, ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalemia were 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 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 is recommended in patients receiving concomitant amlodipine, with dose adjustment of tacrolimus if necessary.

mTOR inhibitors (mammalian target of rapamycin – mammalian target of rapamycin).

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak inhibitor of CYP3A. When used concomitantly with mTOR inhibitors, amlodipine may enhance their effects.

Cyclosporine.

Studies on interactions 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 0–40%) were 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 amlodipine 10 mg and simvastatin 80 mg 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-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 ethanol pharmacokinetics.

Concomitant administration of amlodipine with cimetidine had no effect on amlodipine pharmacokinetics.

Concomitant administration of aluminum/magnesium-containing products (antacids) with a single dose of amlodipine had no significant effect on amlodipine 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.

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 mortality in the future. Data indicate that in patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher with amlodipine compared to placebo.

Patients with hepatic impairment.

The elimination half-life and AUC parameters of amlodipine are increased in patients with impaired liver function; however, there are no specific dosage recommendations. Therefore, treatment in this patient group should be initiated at the lowest dose. Caution is advised both at the start of treatment and during dose escalation. 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.

This patient group should receive standard doses of the drug. 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.

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.

Sodium.

This medicinal product contains 1.6 mg of sodium per tablet. This should be taken into account by patients on a sodium-controlled diet.

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 if the risk associated with the underlying disease outweighs the potential harm of treatment to the mother and fetus.

Reproductive toxicity was observed in animal studies with high doses.

Breastfeeding period.

Amlodipine passes into breast milk. The amount of amlodipine that may be transferred to the infant through maternal milk may range from 3–7% to 15% of the maternal dose. The effects of amlodipine on infants are unknown. When making a decision on continuing breastfeeding or using amlodipine, the benefit of breastfeeding for the child and the benefit of treatment for the mother should be weighed.

Ability to affect reaction speed while 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.

Dosage and Administration

Adults

For the treatment of hypertension and angina, the usual recommended initial dose is 5 mg of amlodipine once daily. Depending on the patient's response to therapy, the dose may be increased up to a maximum dose of 0.1 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.

Experience exists with the use of the drug in combination with thiazide diuretics, alpha-blockers, beta-blockers, or angiotensin-converting enzyme inhibitors in patients with hypertension.

There is no need for dose adjustment when amlodipine is used concomitantly with thiazide diuretics, beta-blockers, or angiotensin-converting enzyme inhibitors.

Children aged 6 years and older with hypertension. The recommended initial dose of amlodipine 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. Use of doses higher than 5 mg daily has not been studied in this patient group.

Elderly patients. No dose adjustment is required for this patient group. However, 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 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 "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, with gradual dose escalation.

Tablets of 5 mg may be divided in half 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. Available data suggest that significant overdose of amlodipine 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 maintaining 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.

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. Data indicate that administration of activated charcoal within 2 hours after ingestion of 10 mg of amlodipine significantly reduces its absorption.

Because amlodipine is highly protein-bound, dialysis is of limited benefit.

Adverse Reactions

The most commonly reported adverse reactions during amlodipine administration include: somnolence, dizziness, headache, palpitations (increased heart rate), flushing, abdominal pain, nausea, ankle swelling, edema, and 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, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 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 – insomnia, mood changes (including anxiety), depression; 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 flutter); very rare – myocardial infarction.

Vascular disorders: common – flushing; uncommon – hypotension; very rare – vasculitis.

Respiratory, thoracic and mediastinal disorders: common – dyspnea; uncommon – rhinitis, cough.

Gastrointestinal disorders: common – abdominal pain, nausea, dyspepsia, intestinal motility disorders (including constipation and diarrhea); 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, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, 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 rare – edema; common – 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 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. 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 parameter abnormalities. No clinically significant changes in pulse rate were observed.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine 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 national regulatory 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. 10 tablets in a blister pack made of aluminum foil (strip). 2 or 3 strips in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Unique Pharmaceuticals Laboratories (a division of J. B. Chemicals and Pharmaceuticals Ltd.)

Manufacturer’s address.

Plot No. 215-219, G.I.D.C. Industrial Area, Panoli – 394 116, District Bharuch, India.