Amlodipine 10 mg. №30

active substance: amlodipine;

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

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

Tablets.

The main physicochemical properties: white or almost white, round, flat tablets with beveled edges with a dividing line on one side.

Selective calcium antagonists with a predominant effect on blood vessels. Dihydropyridine derivatives. ATX code C08S A01.

Amlodipine is a calcium antagonist (a derivative of dihydropyridine) that blocks the flow of calcium ions to the myocardium and smooth muscle cells.

The mechanism of hypotensive action of amlodipine is caused by a direct relaxing effect on vascular smooth muscles. The exact mechanism of the antianginal effect of amlodipine is not well defined, but the following effects play a role:

• Amlodipine dilates peripheral arterioles and thus reduces peripheral resistance (afterload). As the heart rate remains stable, the reduction in cardiac workload leads to a reduction 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. Such expansion increases myocardial oxygen saturation in patients with coronary artery spasm (Prinzmetal’s angina or variant angina).

In patients with arterial hypertension, the use of the drug 1 time per day provides a clinically significant decrease in blood pressure within 24 hours in both lying and standing positions. Because of the slow onset of action of amlodipine, acute arterial hypotension is usually not observed.

In patients with angina pectoris, using one 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 depression of the ST segment. The drug reduces the frequency of angina attacks and reduces the need to use nitroglycerin.

Amlodipine is not associated with any adverse metabolic effects or changes in plasma lipids and can be used in patients with asthma, diabetes and gout.

Absorption/distribution.

After oral administration of therapeutic doses, amlodipine is gradually absorbed into the blood plasma. The absolute bioavailability of the unchanged molecule is approximately 64-80%. The maximum concentration in blood plasma is reached within 6-12 hours after use. The volume of distribution is approximately 21 l/kg; acid dissociation constant (pKa) of amlodipine is 8.6. There are data on conducting in vitro studies have shown that the binding of amlodipine to blood plasma proteins is approximately 97.5%.

The simultaneous use of food does not affect the absorption of amlodipine.

Metabolism/excretion.

The half-life from blood plasma is approximately 35-50 hours. Equilibrium concentration in blood plasma is reached after 7-8 days of continuous use of the drug. Amlodipine is mainly metabolized with the formation of inactive metabolites. About 60% of the administered dose is excreted in the urine, about 10% of which is unchanged amlodipine.

Elderly patients.

The time to reach steady-state plasma concentrations of amlodipine is similar in elderly and 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 the half-life of the drug.

Patients with impaired renal function.

Amlodipine is extensively biotransformed to inactive metabolites. 10% of amlodipine is excreted unchanged in the urine. Changes in the concentration of amlodipine in the blood plasma do not correlate with the degree of renal dysfunction. In patients with impaired renal function, the usual doses of amlodipine can be used. Amlodipine is not removed by dialysis.

Patients with impaired liver function.

Information on the use of amlodipine in patients with impaired liver function is very limited. In patients with hepatic insufficiency, the clearance of amlodipine is reduced, which leads to an increase in the duration of the half-life and an increase in AUC by approximately 40-60%.

Children.

There are data on the conduct of pharmacokinetic studies involving 74 children with arterial hypertension aged 12 to 17 years (also 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) who used amlodipine in doses of 1.25-20 mg per day in 1 or 2 doses. These studies demonstrated that oral clearance in children aged 6 to 12 years and 13 to 17 years was typically 22.5 and 27.4 L/h, respectively, for boys and 16.4 and 21.3 L/h, respectively, for girls There was considerable variability in exposure between patients. Information on patients under 6 years of age is limited.

• Arterial hypertension.
• Chronic stable angina pectoris
• Vasospastic angina (Prinzmetal’s angina).

Known hypersensitivity to dihydropyridines, amlodipine or any other component of the drug; severe arterial hypotension; shock (including cardiogenic shock); obstruction of the outflow tract of the left ventricle (for example, severe aortic stenosis); hemodynamically unstable heart failure after acute myocardial infarction; Children under 6 years old.

Influence of other drugs on amlodipine.

Available data on the safe use of amlodipine with thiazide diuretics, alpha-blockers, beta-blockers, ACE inhibitors, nitrates of prolonged action, sublingual form of nitroglycerin, nonsteroidal anti-inflammatory drugs, antibiotics, oral hypoglycemic drugs.

Data obtained during in vitro studies with human blood plasma indicate that amlodipine has no effect on the binding of the studied drugs (digoxin, phenytoin, warfarin or indomethacin) to blood proteins.

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 may also lead to an increased risk of hypotension. The clinical significance of such changes may be more pronounced in elderly patients. Clinical observation of the patient’s condition and selection of the dose may be necessary.

It is not recommended to use amlodipine and grapefruit or grapefruit juice at the same time, because in some patients the bioavailability of amlodipine may increase, which, in turn, leads to an increase in the hypotensive effect.

CYP3A4 inducers.

There is no information on the effect of CYP3A4 inducers on amlodipine. The simultaneous use of amlodipine and substances that are inducers of CYP3A4 (for example, rifampicin, St. John’s wort) can lead to a decrease in the concentration of amlodipine in the blood plasma, so such combinations should be used with caution.

Dantrolene (infusions).

Fatal ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been observed in animals following intravenous administration of verapamil and dantrolene. Due to the risk of developing hyperkalemia, it is recommended to avoid the use of calcium channel blockers, such as amlodipine, in patients prone to malignant hyperthermia and in the treatment of malignant hyperthermia.

The influence 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 increasing the levels of tacrolimus in the blood when used simultaneously with amlodipine, but the pharmacokinetic mechanism of this interaction has not been fully established. In order to avoid tacrolimus toxicity, when amlodipine is co-administered in patients taking tacrolimus, tacrolimus blood levels should be regularly monitored and the tacrolimus dose adjusted if necessary.

Cyclosporine. 

Interaction studies of cyclosporine and amlodipine when used in healthy volunteers or in other groups were not conducted, except for use in patients with a transplanted kidney, in which a variable increase in the residual concentration of cyclosporine was observed (on average by 0-40%). For renal transplant patients using amlodipine, consideration should be given to monitoring cyclosporine concentrations and, if necessary, reducing the dose of cyclosporine.

Simvastatin. 

Simultaneous administration 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 using amlodipine, the dose of simvastatin should be limited to 20 mg per day.

Sildenafil.

A single dose of 100 mg of sildenafil in patients with essential hypertension did not affect the pharmacokinetics of amlodipine. With simultaneous use of amlodipine and sildenafil as combined therapy, each of the drugs showed a hypotensive effect independently of the other.

Other medicines.

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

Ethanol (alcohol).

Single and repeated administration of 10 mg of amlodipine had no significant effect on the pharmacokinetics of ethanol.

The combined use of amlodipine with cimetidine had no effect on the pharmacokinetics of amlodipine.

The combined use of aluminum/magnesium preparations (antacids) with a single dose of amlodipine did not have a significant effect on the pharmacokinetics of amlodipine.

Laboratory tests.

The effect on laboratory test results is unknown.

The safety and efficacy of Amlodipine 10 mg. 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 future cardiovascular events and death. There are data that in patients with severe heart failure (class III and IV according to the NYHA classification) when using amlodipine, the frequency of pulmonary edema was higher compared to placebo.

Patients with impaired liver function. 

Amlodipine 10 mg. half-life and AUC parameters increase in patients with impaired liver function; there are no recommendations regarding doses of the drug. Therefore, this category of patients should start using the drug with the lowest dose. Care should be taken both at the beginning of the use of the drug and when increasing the dose. Patients with severe hepatic impairment may require slow titration and close monitoring of the patient’s condition.

Elderly patients. 

Increasing the dose of the drug in this category of patients should be done with caution.

Patients with renal failure. 

Usual doses of the drug should be used for this category of patients. 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 10 mg. does not affect the results of laboratory studies.

It is not recommended to use amlodipine together with grapefruit or with grapefruit juice, because in some patients the bioavailability may be increased, which will lead to an increase in the hypotensive effect of the drug.

Amlodipine may have minor or moderate effects on the ability to drive or operate machinery. The speed of reaction may be reduced in the presence of such symptoms as dizziness, headache, confusion or nausea.

Care should be taken, especially at the beginning of therapy.

The safety of using Amlodipine 10 mg. in women during pregnancy has not been established. It is recommended to use amlodipine during pregnancy only in cases where there is no safer alternative, and the risk associated with the disease itself exceeds the possible harm from treatment for the mother and the fetus.

In animal studies, reproductive toxicity was observed at high doses.

Breastfeeding period.

It is not known whether amlodipine passes into breast milk. When deciding to continue breastfeeding or to use amlodipine, it is necessary to evaluate the benefits of breastfeeding for the child and the benefits of using the drug for the mother.

Fertility

Reversible biochemical changes in the sperm head have been reported in some patients with calcium channel blockers. There is insufficient clinical information regarding the potential effect of amlodipine on fertility.

Adults 

For the treatment of hypertension and angina pectoris, the usual recommended starting dose is 5 mg of amlodipine once daily. Depending on the patient’s response to therapy, the dose can be increased to a maximum dose of 10 mg once a day.

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 beta-blockers.

There is experience in using 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 to adjust the dose of the drug during simultaneous use with thiazide diuretics, beta-blockers and angiotensin-converting enzyme inhibitors.

Children over 6 years of age with arterial hypertension. The recommended initial dose of amlodipine for this category of patients is 2.5 mg once a day. If the required level of blood pressure is not achieved within 4 weeks, the dose can be increased to 5 mg per day. The use of the drug in doses higher than 5 mg for this category of patients has not been studied.

Elderly patients. There is no need to adjust the dose for this category of patients. Increasing the dose should be done with caution.

Patients with impaired renal function. It is recommended to use the usual doses of the drug, since changes in the concentration of amlodipine in the blood plasma are not related to the degree of severity of renal failure. Amlodipine is not removed by dialysis.

Patients with impaired liver function. Doses of the drug for use in patients with impaired liver function from mild to moderate severity have not been established, so the selection of the dose should be carried out with caution and use should be started with the lowest dose. The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. For patients with severe hepatic impairment, amlodipine should be started at the lowest dose and gradually increased.

5 mg tablets can be split in half to obtain a 2.5 mg dose.

Amlodipine 10 mg. can be used by children aged 6 years and older.

The effect of amlodipine on blood pressure in patients under 6 years of age is unknown.

The experience of intentional drug overdose is limited.

Symptoms of overdose. The available information suggests that a significant overdose of amlodipine will lead to excessive peripheral vasodilatation and possibly to reflex tachycardia. Significant and possibly prolonged systemic hypotension, including fatal shock, has been reported.

Treatment. Clinically significant hypotension caused by an overdose of Amlodipine 10 mg. requires active support of the cardiovascular system, including frequent monitoring of cardiac and respiratory functions, elevation of the lower extremities, monitoring of the volume of circulating fluid and urination.

Vasoconstrictor drugs can be used to restore blood vessel tone and blood pressure, making sure there are no contraindications to their use. Intravenous administration of calcium gluconate may be useful in reversing the effects of calcium channel blockade.

In some cases, gastric lavage may be helpful. There are data that the use of activated carbon within 2 hours after administration of 10 mg of amlodipine significantly reduces its absorption.

Since amlodipine is highly bound to blood plasma proteins, the effect of dialysis is insignificant.

From the blood and lymphatic system: leukocytopenia, thrombocytopenia.

From the side of the immune system : allergic reactions.

From the side of metabolism and alimentary disorders : hyperglycemia.

Mental disorders: insomnia, mood changes (including anxiety), depression, confusion.

From the side of the nervous system: drowsiness, dizziness, headache (mainly at the beginning of treatment), tremor, dysgeusia, syncope, hypoesthesia, paresthesia, hypertension, peripheral neuropathy.

On the part of the organs of vision: visual disturbances (including diplopia).

From the organs of hearing and labyrinth: ringing in the ears.

From the side of the heart: increased heart rate, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation).

From the side of blood vessels: hot flashes, arterial hypotension, vasculitis.

Respiratory, thoracic and mediastinal disorders: dyspnea, rhinitis, cough.

From the gastrointestinal tract: abdominal pain, nausea, vomiting, dyspepsia, intestinal motility disorders (including constipation and diarrhea), dry mouth, pancreatitis, gastritis, gum hyperplasia.

From the side of the hepatobiliary system: hepatitis, jaundice, increase in the level of liver enzymes (which was most often associated with cholestasis).

From the skin and subcutaneous tissue: alopecia, purpura, skin discoloration, increased sweating, itching, rash, exanthema, angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke’s edema, photosensitivity.

On the part of the musculoskeletal and connective tissues: swelling of the lower legs, arthralgia, myalgia, muscle spasms, back pain.

On the part of the kidneys and urinary tract: impaired urination, nocturia, increased frequency of urination.

From the reproductive system and mammary glands: impotence, gynecomastia.

General disorders and conditions at the injection site: edema, increased fatigue, chest pain, asthenia, pain, malaise.

Research. 

Infrequent: increase or decrease in body weight.

Exceptional cases of extrapyramidal syndrome have been reported.

Children.

Amlodipine 10 mg. is well tolerated when used in children. The adverse reaction profile was similar to that observed in adults. In the studies, the following adverse reactions were most often reported: headache, dizziness, dilation of blood vessels, epistaxis, abdominal pain, asthenia.

Most adverse reactions were mild or moderate. Severe adverse reactions (predominantly headache) were observed in 7.2% in the 2.5 mg amlodipine group, in 4.5% in the 5 mg amlodipine group, and in 4.6% in the placebo group. The most common reason for exclusion from the study was uncontrolled hypertension. In no case was exclusion from the study caused by deviations of laboratory parameters from the norm. No significant changes in heart rate were recorded.

Reporting of suspected adverse reactions. 

The reporting of suspected adverse reactions after the registration of a medicinal product is important. This makes it possible to continuously monitor the ratio between benefits and risks associated with the use of this medicinal product. Physicians should report any suspected adverse reactions as required by law.

3 years.

Store in the original packaging at a temperature not higher than 30 °C.

Keep out of the reach of children.

10 tablets each in a contoured blister pack made of aluminum foil. 3 strips in a cardboard box.