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, 1 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 asthma, diabetes mellitus, and gout.
Pharmacokinetics
Absorption/distribution. After oral administration in therapeutic doses, amlodipine 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 blood 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 elderly patients and in adult patients. The clearance of amlodipine is usually slightly reduced, which in elderly patients leads to an increase in the area under the concentration-time curve (AUC) and T ½.
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 very limited. In patients with hepatic insufficiency, clearance of the drug is reduced, resulting in an increase in the half-life and an increase in 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 patients with angina pectoris and angina pectoris, the usual starting dose of Aladin 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 alone or in combination with other antianginal drugs in case of resistance to nitrates and/or adequate doses of beta-blockers.
There is experience of using the drug in combination with thiazide diuretics, alpha- and beta-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, beta-blockers and ACE inhibitors.
Children aged 6 years and older with hypertension. The recommended initial dose of Aladin for this category of patients is 2.5 mg 1 time per day. 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 of 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 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
From the blood and lymphatic system: thrombocytopenia, leukocytopenia;
from the immune system: allergic reactions;
metabolic and nutritional disorders: hyperglycemia;
Mental: insomnia, mood swings (including anxiety), depression, confusion;
from the nervous system: drowsiness, dizziness, headache (mainly at the beginning of treatment), tremor, dysgeusia, syncope, hypoesthesia, paresthesia, hypertonicity, peripheral neuropathy;
On the part of the organs of vision: visual impairment (including diplopia), lacrimation;
From the side of the organs of hearing and labyrinth: ringing in the ears;
Cardiac: palpitations, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation);
Vascular: hot flashes, hypotension, vasculitis;
Respiratory, thoracic and mediastinal disorders: dyspnea, rhinitis, cough;
Gastrointestinal: nausea, vomiting, abdominal pain, dyspepsia, dry mouth, intestinal motility disorders (including constipation and diarrhea), pancreatitis, gastritis, gingival hyperplasia;
Hepatobiliary system: hepatitis, jaundice, increased liver enzymes (most often associated with cholestasis);
Skin and subcutaneous tissue disorders: angioedema (Quincke's edema), rash, itching, erythema multiforme, rash, urticaria, alopecia, purpura, skin discoloration, increased sweating, photosensitivity, exfoliative dermatitis, Stevens-Johnson syndrome;
Musculoskeletal and connective tissue disorders: swelling of the lower legs, joint pain, muscle pain, muscle cramps, back pain;
from the kidneys and urinary tract: nocturia, urinary disorders, increased frequency of urination;
from the reproductive system and mammary glands: gynecomastia, impotence;
general disorders: edema, fatigue, asthenia, pain, chest pain, malaise;
research: increase or decrease in body weight.
Exceptional cases of extrapyramidal syndrome have been reported.
Special instructions
The drug should be started at the lowest dose. Caution should be exercised both when starting the drug and when increasing the dose. Patients with severe hepatic impairment may require slow dose titration and close monitoring of the patient's health.
Throughout the entire period of treatment, it is necessary to monitor body weight and sodium intake, prescribe an appropriate diet, and monitor blood pressure daily.
The safety and efficacy of amlodipine in hypertensive crisis have not been evaluated.
Use in patients with heart failure. Aladin should be used with caution in this category of patients. In patients with severe heart failure (class III and IV according to the NYHA classification), the incidence of pulmonary edema was higher when using amlodipine compared to placebo. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they increase the risk of cardiovascular events and mortality in the future.
Use in patients with impaired liver function. T ½ of amlodipine and AUC parameters are longer in patients with impaired liver function, there are no recommendations for the dosage of the drug. Therefore, this category of patients should start taking the drug with the lowest dose. Caution should be exercised both at the beginning of the drug and during dose increases. Patients with severe liver failure may require slow dose selection and careful monitoring of their health.
Use in elderly patients. Increasing the dose of the drug in this category of patients should be done with caution.
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.
Use during pregnancy or breastfeeding. The safety of amlodipine in women 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.
During animal tests, reproductive toxicity was observed when using high doses of the drug.
Breastfeeding: It is not known whether amlodipine is excreted in human milk. A decision must be made whether to continue breastfeeding or to use amlodipine, taking into account the benefit of breastfeeding for the child and the benefit of the drug for the mother.
Fertility: Reversible biochemical changes in the sperm head have been reported in some patients receiving calcium channel blockers. There is insufficient clinical information on the potential effect of amlodipine on fertility.
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 rate when driving vehicles or operating other mechanisms. Aladin 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 drugs on amlodipine
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 result in a substantial increase in amlodipine exposure, which may increase the risk of hypotension. The clinical significance of these changes may be more pronounced in elderly patients. Clinical monitoring of the patient and dose adjustment may be necessary.
It is not recommended to use amlodipine simultaneously with grapefruit or grapefruit juice, since in some patients the bioavailability of amlodipine may increase, which, in turn, leads to increased hypotensive effect.
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 the treatment of 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 when co-administered with amlodipine, tacrolimus blood levels should be monitored and the dosage adjusted if necessary.
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. In 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.
The results of clinical drug interaction studies indicate that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, ethanol (alcohol), or warfarin.
Overdose
Experience with intentional overdose of the drug is limited.
Symptoms of overdose: Available information suggests that a significant overdose of Aladin will result in excessive peripheral vasodilation and possibly reflex tachycardia. Significant and possibly prolonged systemic hypotension, including shock with fatal outcome, has been reported.
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.
