Pharmacological properties
Pharmacodynamics. Amlodipine is a calcium antagonist (dihydropyridine derivative) that blocks the entry of calcium ions into the myocardium and smooth muscle cells.
The mechanism of the hypotensive action of amlodipine is due to a direct relaxing effect on vascular smooth muscle. The exact mechanism of the antianginal effect of amlodipine is not well understood, but the effects listed below play a role.
Amlodipine dilates peripheral arterioles and thus reduces peripheral resistance (afterload). Since the heart rate remains stable, the reduced workload on the heart leads to a decrease in energy consumption and myocardial oxygen demand.
Dilation of the main coronary arteries and coronary arterioles (normal and ischemic) may also play a role in the mechanism of action of amlodipine. This dilation increases myocardial oxygen saturation in patients with coronary artery spasm (Prinzmetal's angina or variant angina).
In patients with hypertension, once-daily administration of the drug provides a clinically significant reduction in blood pressure for 24 hours in both the supine and standing positions. Due to the slow onset of action of amlodipine, acute arterial hypotension is usually not observed.
In patients with angina pectoris, a single daily dose of the drug increases the total time of physical exertion, the time to the onset of angina pectoris, and the time to 1 mm of ST-segment depression. The drug reduces the frequency of angina attacks and reduces the need for nitroglycerin.
Amlodipine is not associated with any adverse metabolic effects or changes in plasma lipid levels and can be used in patients with bronchial asthma, diabetes mellitus, and gout.
Pharmacokinetics
Absorption/distribution. After oral administration of amlodipine in therapeutic doses, it is gradually absorbed into the blood plasma. The absolute bioavailability of the unchanged molecule is approximately 64-80%. C max in blood plasma is achieved within 6-12 hours after administration. The volume of distribution is approximately 21 l/kg body weight; the acid dissociation constant (pKa) of amlodipine is 8.6. The binding of amlodipine to plasma proteins is approximately 97.5%.
Concomitant food intake does not affect the absorption of amlodipine.
Metabolism/Excretion. T½ from blood plasma is approximately 35-50 hours. Steady-state plasma concentrations are achieved after 7-8 days of continuous administration. Amlodipine is primarily metabolized to inactive metabolites. About 60% of the administered dose is excreted in the urine, of which about 10% is unchanged amlodipine.
Elderly patients. The time to reach steady-state plasma concentrations of amlodipine is similar in the elderly and in adult patients. The clearance of amlodipine is usually slightly reduced, which in elderly patients leads to an increase in AUC and T½ of the drug.
Patients with renal impairment. Amlodipine is extensively biotransformed to inactive metabolites. 10% of amlodipine is excreted unchanged in the urine. Changes in plasma amlodipine concentrations do not correlate with the degree of renal impairment. Amlodipine can be used in patients with renal impairment at normal doses. Amlodipine is not removed by dialysis.
Patients with hepatic impairment. Information on the use of amlodipine in patients with hepatic impairment is extremely limited. In subjects with hepatic insufficiency, clearance of the drug is reduced, resulting in an increase in T½ and AUC by approximately 40-60%.
Children. Typically, oral clearance in children aged 6-12 and 13-17 years was 22.5 and 27.4 l/h, respectively, for boys and 16.4 and 21.3 l/h, respectively, for girls. There is considerable variability in exposure between patients. Information in patients under 6 years of age is limited.
Indication
Ag, chronic stable angina, vasospastic angina (Prinzmetal's angina).
Application
Adults. For the treatment of angina pectoris and angina pectoris, the usual starting dose of Amlodipine-Farmak is 5 mg once daily. Depending on the patient's response to therapy, the dose may be increased to a maximum of 10 mg once daily.
In patients with angina pectoris, the drug can be used as monotherapy or in combination with other antianginal drugs in case of resistance to nitrates and/or adequate doses of β-adrenergic blockers.
There is experience of using the drug in combination with thiazide diuretics, α- and β-blockers, or ACE inhibitors in patients with hypertension.
There is no need to adjust the dose of the drug when used simultaneously with thiazide diuretics, β-adrenergic blockers and ACE inhibitors.
Children over 6 years of age with hypertension. The recommended initial dose of Amlodipine-Farmak for this category of patients is 2.5 mg 1 time per day (to be used in the appropriate dosage). If the required blood pressure level is not achieved within 4 weeks, the dose can be increased to 5 mg/day. The use of the drug in doses higher than 5 mg for this category of patients has not been studied.
Patients with impaired renal function. It is recommended to use the drug in normal doses, since changes in the concentration of amlodipine in the blood plasma are not associated with the severity of renal failure. Amlodipine is not excreted by dialysis.
Patients with hepatic impairment. Doses of the drug for use in patients with mild to moderate hepatic impairment have not been established, therefore dose selection should be carried out with caution and use should be started with the lowest dose (see Features of use and excipients, Pharmacokinetics).
The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. In patients with severe hepatic impairment, amlodipine should be started at the lowest dose and titrated gradually.
Contraindication
Known hypersensitivity to dihydropyridines, amlodipine or to any component of the drug; severe arterial hypotension; shock (including cardiogenic shock), obstruction of the left ventricular outflow tract (e.g. severe aortic stenosis); hemodynamically unstable heart failure after acute myocardial infarction.
Side effects
The most commonly reported adverse reactions with amlodipine are drowsiness, dizziness, headache, palpitations, hot flashes, abdominal pain, nausea, leg swelling, edema, and fatigue.
Adverse reactions reported with amlodipine are listed below by system organ class and frequency: very common (≥1/10), common (≥1/100 to 1/10), uncommon (≥1/1,000 to ≤1/100), rare (≥1/10,000 to ≤1/1,000), very rare (≤1/10,000):
From the blood and lymphatic system: very rarely - leukocytopenia, thrombocytopenia;
from the immune system: very rarely - allergic reactions;
Metabolism and nutritional disorders: very rarely - hyperglycemia;
Mental disorders: infrequently - depression, mood changes (including anxiety), insomnia; rarely - confusion;
Nervous system: often - drowsiness, dizziness, headache (mainly at the beginning of treatment); infrequently - tremor, dysgeusia, syncope, hypoesthesia, paresthesia; very rarely - hypertonicity, peripheral neuropathy;
On the part of the organ of vision: often - visual impairment (including diplopia);
From the side of the organs of hearing and labyrinth: infrequently - ringing in the ears;
Cardiac disorders: often - palpitations; infrequently - arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation); very rarely - myocardial infarction;
Vascular disorders: often - hot flashes; infrequently - arterial hypotension; very rarely - vasculitis;
Respiratory, thoracic and mediastinal disorders: often - dyspnea; infrequently - cough, rhinitis;
From the digestive tract: often - abdominal pain, nausea, dyspepsia, intestinal motility disorders (including diarrhea and constipation); infrequently - vomiting, dry mouth; very rarely - pancreatitis, gastritis, gingival hyperplasia;
Hepatobiliary system: very rarely - hepatitis, jaundice, increased liver enzymes (most often associated with cholestasis);
Skin and subcutaneous tissue disorders: infrequently - alopecia, purpura, skin discoloration, increased sweating, itching, rash, exanthema, urticaria; very rarely - angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity;
Musculoskeletal and connective tissue disorders: often - swelling of the lower legs, muscle cramps; infrequently - arthralgia, myalgia, back pain;
From the kidneys and urinary tract: infrequently - urination disorders, nocturia, increased urinary frequency.
Reproductive system and breast disorders: infrequently - impotence, gynecomastia;
General disorders and administration site conditions Very common - edema; common - fatigue, asthenia; uncommon - chest pain, pain, malaise;
Research: infrequently - increase or decrease in body weight.
Exceptional 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 of 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 treated with 2.5 mg amlodipine, 4.5% with 5 mg amlodipine, and 4.6% in the placebo group. The most common reason for discontinuation was uncontrolled hypertension. No laboratory abnormalities were the reason for discontinuation. No significant changes in heart rate were noted.
Reporting of suspected adverse reactions. Reporting of suspected adverse reactions after the registration of a medicinal product is important. This allows for continuous monitoring of the benefit/risk balance associated with the use of this medicinal product. Physicians should report any suspected adverse reactions in accordance with legal requirements.
Special instructions
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 because they may increase the risk of future cardiovascular events and mortality.
Patients with impaired liver function. T ½ of amlodipine and AUC parameters are higher in patients with impaired liver function; there are no recommendations for doses of the drug. Therefore, this category of patients should start taking the drug with the lowest dose. Caution is required both at the beginning of the drug and when increasing the dose. Patients with severe liver failure may require slow dose selection and careful monitoring of their health.
Elderly patients: Increasing the dose of the drug in this category of patients should be done with caution.
Patients with renal insufficiency. This category of patients should use the drug in normal doses. Changes in the concentration of amlodipine in the blood plasma do not correlate with the degree of renal dysfunction. Amlodipine is not removed by dialysis.
Amlodipine does not affect laboratory test results. It is not recommended to use amlodipine with grapefruit or grapefruit juice, since in some patients the bioavailability may be increased, which will lead to an increase in the hypotensive effect of the drug.
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.
This medicinal product contains 1 mmol sodium (23 mg), i.e. essentially sodium-free.
The drug Amlodipine-Farmak contains lactose, therefore patients with rare hereditary diseases of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not use this drug.
Use during pregnancy or breastfeeding. The safety of amlodipine during pregnancy has not been established.
The use of amlodipine during pregnancy is recommended only in cases where there is no safer alternative and the risk associated with the disease itself outweighs the possible harm from treatment for the mother and fetus.
In animal studies, reproductive toxicity was observed at high doses.
Breastfeeding. Amlodipine has been identified in breastfed infants whose mothers were taking the drug. The proportion of the initial maternal dose received by the infant has been estimated to range from 3-7%, with a maximum of 15%. The effect of amlodipine on the infant is unknown.
When deciding whether to continue breastfeeding or to use amlodipine, the benefit of breastfeeding for the child and the benefit of the drug for the mother should be assessed.
Children. The drug should be used in children aged 6 years and older. The effect of amlodipine on blood pressure in patients under 6 years of age is unknown.
Ability to influence the reaction speed when driving vehicles or operating other mechanisms. Amlodipine-Farmak may have a minor or moderate influence on the ability to drive vehicles or operate other mechanisms. Caution should be exercised, especially at the beginning of therapy.
Reaction speed may be reduced in the presence of symptoms such as dizziness, headache, confusion or nausea.
Interactions
Effects of other medicinal products on amlodipine. There is evidence of the safe use of amlodipine with thiazide diuretics, α- and β-receptor blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
Data obtained during in vitro studies of human blood plasma indicate that amlodipine has no effect on the binding of the studied drugs (digoxin, phenytoin, warfarin or indomethacin) to blood proteins.
CYP 3A4 inhibitors. Concomitant use of amlodipine and potent or moderate CYP 3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may lead to a substantial increase in amlodipine exposure, which also increases the risk of hypotension. The clinical significance of such changes may be more pronounced in the elderly. Clinical monitoring of the patient's health and dose adjustment may be necessary.
CYP 3A4 inducers. There is no information on the effect of CYP 3A4 inducers on amlodipine. Concomitant use of amlodipine and substances that are CYP 3A4 inducers (e.g. rifampicin, St. John's wort) may lead to a decrease in the plasma concentration of amlodipine, therefore such combinations should be used with caution.
Dantrolene (infusion): Fatal ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been reported in animals following the administration of verapamil and intravenous dantrolene. Due to the risk of hyperkalemia, it is recommended that calcium channel blockers, such as amlodipine, be avoided in patients predisposed to malignant hyperthermia and in malignant hyperthermia.
Effect of amlodipine on other medicinal products. The hypotensive effect of amlodipine potentiates the hypotensive effect of other antihypertensive agents.
Tacrolimus. There is a risk of increased blood levels of tacrolimus when co-administered with amlodipine, but the pharmacokinetic mechanism of this interaction has not been fully established. To avoid tacrolimus toxicity, patients taking tacrolimus should have their blood levels monitored regularly and their tacrolimus dose adjusted if necessary when co-administered with amlodipine.
mTOR (mammalian target of rapamycin) inhibitors. mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP 3A. Amlodipine is a weak inhibitor of CYP 3A. When amlodipine is used concomitantly with mTOR inhibitors, it may potentiate the effects of the latter.
Cyclosporine: No interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations, except in renal transplant patients, where variable increases in cyclosporine trough concentrations (mean 0-40%) were observed. For renal transplant patients receiving amlodipine, monitoring of cyclosporine concentrations should be considered and, if necessary, a reduction in the cyclosporine dose.
Simvastatin: Coadministration of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. For patients taking amlodipine, the dose of simvastatin should be limited to 20 mg/day.
Sildenafil. Single doses of 100 mg sildenafil in patients with essential hypertension did not affect the pharmacokinetics of amlodipine. When amlodipine and sildenafil were administered as single-dose combination therapy, each drug exerted an independent hypotensive effect.
Other medicinal products: Results of clinical drug interaction studies indicate that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Ethanol (alcohol). Single and multiple doses of 10 mg amlodipine did not significantly affect the pharmacokinetics of ethanol. Concomitant administration of amlodipine with cimetidine did not affect the pharmacokinetics of amlodipine. Concomitant administration of aluminum/magnesium preparations (antacids) with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
Laboratory tests: The effect on laboratory test results is unknown.
Overdose
Experience with intentional overdose of the drug is limited.
Symptoms of overdose: Available information suggests that a significant overdose of Amlodipine-Farmak will result in excessive peripheral vasodilation and possibly reflex tachycardia. Significant and possibly prolonged systemic hypotension, including shock with fatal outcome, has been reported.
Treatment: Clinically significant hypotension caused by amlodipine overdose requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of extremities, monitoring of circulating fluid volume and urine output.
Vasoconstrictors can be used to restore vascular tone and blood pressure, making sure there are no contraindications to their use. The use of calcium gluconate intravenously may be useful for neutralizing the effects of calcium channel blockade.
Gastric lavage may be useful in some cases. Administration of activated charcoal to healthy volunteers within 2 hours of administration of 10 mg amlodipine significantly reduced its absorption.
Since amlodipine is extensively protein bound, the effect of dialysis is negligible.
Storage conditions
In the original packaging at a temperature not exceeding 25 °C.
