Amlodipine-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Amlodipine-Teva (Amlodipine-Teva)

Composition:

Active substance: amlodipine;

1 tablet contains 5 mg or 10 mg of amlodipine (as amlodipine besylate);

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

Pharmaceutical form. Tablets.

Main physicochemical properties:

5 mg tablets: white, round tablets, 8 mm in diameter, slightly convex, with a break line and embossing "A5" on one side and slightly convex, smooth on the other side;

10 mg tablets: white, round tablets, 11 mm in diameter, slightly convex, with a break line and embossing "A10" on one side and slightly convex, smooth on the other side.

Pharmacotherapeutic group. Cardiovascular agents. 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 transmembrane influx of calcium ions into vascular smooth muscle and myocardial cells.

The antihypertensive mechanism of action of amlodipine is due to direct relaxation of vascular smooth muscle. The precise mechanism of the antianginal effect of amlodipine has not been fully established; however, amlodipine reduces total ischemic burden through the following effects.

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

Dilation of major coronary arteries and coronary arterioles (both normal and ischemic) increases myocardial oxygen supply in patients with coronary artery spasm (Prinzmetal’s angina or variant angina).

Clinical efficacy and safety.

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 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 in therapeutic doses, amlodipine is well absorbed, with peak plasma concentration (Cmax) reached within 6–12 hours after dose intake. Absolute bioavailability of the unchanged molecule is approximately 64–80%. Volume of distribution is approximately 21 L/kg, and 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 bioavailability of amlodipine.

Metabolism/Excretion.

The terminal elimination half-life from plasma is approximately 35–50 hours, consistent with once-daily dosing. Steady-state plasma concentrations are achieved after 7–8 days of continuous drug administration. Amlodipine is primarily metabolized in the liver 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 younger patients. Amlodipine clearance is generally slightly reduced, leading to increased area under the plasma concentration-time curve (AUC) and prolonged elimination half-life in elderly patients. Increased AUC and elimination half-life observed in patients with congestive heart failure corresponded to the age characteristics of the study population.

Patients with renal impairment.

Amlodipine is extensively biotransformed to inactive metabolites. About 10% of amlodipine is excreted unchanged in urine. Plasma concentrations of amlodipine do not correlate with the degree of renal impairment. Standard doses of amlodipine can be used in patients with impaired renal function. 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.

A population pharmacokinetic study was 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. Following oral administration, typical clearance (CL/F) was 22.5 and 27.4 L/hour in boys aged 6–12 and 13–17 years, respectively, and 16.4 and 21.3 L/hour in girls aged 6–12 and 13–17 years, respectively. There is considerable interpatient 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 safety data support the use of amlodipine with thiazide diuretics, alpha-blockers, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, long-acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and oral hypoglycemic agents.

In vitro studies in human plasma indicate that amlodipine does not affect the protein binding of tested medicinal products (digoxin, phenytoin, warfarin, or indomethacin).

Inhibitors of CYP3A4.

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 and 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.

Clarithromycin is a CYP3A4 inhibitor. In patients receiving both clarithromycin and amlodipine, the risk of arterial hypotension is increased. Close monitoring is recommended when amlodipine and clarithromycin are used concomitantly.

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.

Inducers of CYP3A4.

Plasma concentrations of amlodipine may vary following concomitant use with known CYP3A4 inducers. Therefore, blood pressure monitoring and dose adjustment should be performed both during and after concomitant therapy, particularly 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 during treatment of malignant hyperthermia.

Effect of amlodipine on other medicinal products.

The antihypertensive effect of amlodipine may potentiate the hypotensive 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 during concomitant use with amlodipine, regular monitoring of tacrolimus blood levels is required, and dose adjustment of tacrolimus may be necessary.

Mammalian target of rapamycin (mTOR) inhibitors.

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 groups, except in kidney transplant patients, in whom variable increases in trough cyclosporine concentrations (on average by 0–40%) have been observed. In kidney transplant patients receiving amlodipine, monitoring of cyclosporine concentrations should be considered, and cyclosporine dosage may need to be 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.

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, 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.

It is unknown whether amlodipine affects the results of laboratory tests.

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 functional class III–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 increased in patients with hepatic impairment; however, no specific dosage recommendations are available. Therefore, treatment in this patient group should be initiated at the lowest dose. Caution is required both when starting therapy and when increasing the dose. Patients with severe hepatic impairment may require slow dose titration and careful monitoring.

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 interfere with laboratory test results.

Elderly patients.

Dosage increases in this patient group should be performed cautiously.

Other.

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

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

The safety of amlodipine use in pregnant women has not been established.

Amlodipine should be used during pregnancy only if no safer alternative exists and if the risk associated with the disease itself outweighs the potential risk of harm to the pregnant woman and fetus.

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

Breastfeeding period.

Amlodipine is excreted in human breast milk. The infant dose relative to maternal dose is estimated to range 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 carefully weighed.

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 limited. In one study, impaired fertility was observed in male rats.

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.

Method of administration and dosage.

For oral use. The tablet can be divided into equal doses.

If the physician has prescribed taking ½ (half) of a tablet daily, do not use any tablet-splitting devices. Follow the instructions below:

• Place the tablet on a flat, hard surface (e.g., a table or countertop) with the imprint facing upward;
• Break the tablet by pressing with the index fingers of both hands along the break line.

Adults.

For the treatment of hypertension and angina, the usual initial dose of amlodipine 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.

For patients with angina, the drug may be used as monotherapy or in combination with other antianginal medications 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 hypertension.

There is no need to adjust the dose of the drug when used concomitantly with thiazide diuretics, beta-blockers, or ACE 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 is not achieved within 4 weeks, the dose may be increased to 5 mg daily. The use of doses higher than 5 mg has not been studied in this patient group.

Elderly patients.

Amlodipine is similarly well tolerated in elderly and younger patients when used at comparable doses. Elderly patients should be prescribed the usual doses; however, dose escalation should be done cautiously.

Patients with renal impairment.

The usual doses are recommended, as amlodipine plasma concentration is not related to the severity of renal impairment. Amlodipine is not removed by dialysis.

Patients with hepatic impairment.

Dosage regimens for amlodipine in 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"). 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.

Children.

The drug can 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: Available data suggest that significant overdose of amlodipine may lead 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 manifest with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Early resuscitation measures (including fluid overload) to support perfusion and cardiac output may act as triggering factors.

Treatment: Clinically significant arterial hypotension due to amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory functions, placing the patient in a supine position, elevation of the lower limbs, and monitoring of circulating fluid volume and urine 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 to healthy volunteers within 2 hours after 10 mg amlodipine intake significantly reduced its absorption.

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

Adverse reactions.

When amlodipine was used, the most commonly reported adverse reactions were: somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, leg swelling, edema, and fatigue. During treatment with amlodipine, the following adverse reactions have been reported according to the 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); frequency not known (cannot be estimated from available data).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

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, flushing; uncommon – arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation), hypotension; very rare – myocardial infarction, 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 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, toxic epidermal necrolysis, 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 – micturition disorder, nocturia, increased frequency of urination.

Reproductive system and breast disorders: uncommon – impotence, gynecomastia.

General disorders: very common – edema; common – fatigue, asthenia; uncommon – chest pain, pain, malaise.

Investigations: uncommon – weight gain or weight loss.

There have been exceptional cases of extrapyramidal syndrome development.

Children.

The adverse reaction profile was similar to that observed in adults. Reported adverse reactions include: headache, dizziness, vasodilation, epistaxis, abdominal pain, asthenia. Most adverse reactions were mild or moderate in severity.

Reporting of suspected adverse reactions. All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua/.

Shelf life. 5 years.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep in the original packaging. Keep the blister pack in the cardboard box. Store in a place inaccessible to children.

Packaging. 10 tablets per blister; 3 or 9 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Teva Pharmaceutical Works Private Limited Company.

Manufacturer's address and location of operations.

Site 1; Pallagi str. 13, H-4042 Debrecen, Hungary.