Amlodipine SAN tablets 5 mg. №30

active substance: amlodipine;

1 tablet contains amlodipine besylate 6.935 mg, which is equivalent to amlodipine 5 mg; 

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

Tablets.

The main physical and chemical properties: flat-cylindrical tablets with beveled edges and a line, white or almost white in color.

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

Amlodipine is a calcium antagonist (dihydropyridine derivative) that blocks the influx 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.

1. 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.
2. 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 application. The volume of distribution is approximately 21 l/kg; acid dissociation constant (pKa) of amlodipine is 8.6. 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 concentrations of amlodipine in blood plasma 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 curve “concentration/time” (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. Typically, oral clearance in children aged 6 to 12 years and 13 to 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 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 medicinal product; 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.

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.

It is known that the data obtained in the course of in vitro studies with human blood plasma indicate that amlodipine has no effect on the binding of the investigated 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 grapefruits 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). 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. In patients with a transplanted kidney, 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 in hypertensive crisis have not been evaluated.

Patients with heart failure. Amlodipine should be used with caution in this category of patients. There is information that in patients with severe heart failure (class III and IV according to the NYHA classification) when using amlodipine, the incidence of pulmonary edema was higher than when using 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 death. 

Patients with impaired liver function. Amlodipine half-life and AUC parameters are higher in patients with impaired liver function; there are no recommendations regarding doses of the medicinal product. Therefore, this category of patients should start using the drug with the lowest dose. You should be careful both at the beginning of the use of the drug and during the increase of 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 Amlodipine SAN in this category of patients should be done with caution.

Patients with renal failure. For this category of patients, the usual doses of the drug should be used. 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 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.

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.

Amlodipine SAN tablets may have a minor or moderate effect on the ability to drive or operate machinery.

Since the reaction rate may be reduced in the presence of symptoms such as dizziness, headache, confusion or nausea, caution should be exercised, especially at the beginning of therapy.

The safety of using Amlodipine SAN tablets in women during pregnancy has not been established. 

It is recommended to use Amlodipine SAN tablets during pregnancy only in those cases when 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. 

Breastfeeding period. It is not known whether amlodipine passes into breast milk. When making a decision 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.

Adults For the treatment of arterial hypertension and angina pectoris, the usual initial dose of Amlodipine SAN tablets is 5 mg once a day. 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, Amlodipine SAN tablets 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 when used simultaneously with thiazide diuretics, beta-blockers and angiotensin-converting enzyme inhibitors.

Children over 6 years of age with arterial hypertension . The recommended initial dose of the drug 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 medicinal product 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 a mild to moderate degree have not been established, therefore the selection of the dose should be carried out with caution and the use of the drug should be started with the lowest dose in the dose range. 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.

Amlodipine SAN tablets can be used by children aged 6 and over. 

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: Available information suggests that a significant overdose of Amlodipine SAN will result in excessive peripheral vasodilatation and possibly reflex tachycardia. Significant and possibly prolonged systemic hypotension, including fatal shock, has been reported.

Treatment: clinically significant arterial hypotension caused by an overdose of amlodipine 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 urine output. 

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. The use of activated charcoal in healthy volunteers within 2 hours after administration of 10 mg of amlodipine significantly reduced its absorption.

Since amlodipine is largely bound to blood proteins, the effect of dialysis is negligible.

When using Amlodipine SAN tablets, the following side effects were most often reported: drowsiness, dizziness, headache, increased heart rate, hot flashes, abdominal pain, nausea, leg swelling, swelling and increased fatigue.

From the blood and lymphatic system: leukocytopenia, thrombocytopenia.

From the side of the immune system : allergic reactions.

On the part of the psyche: depression, mood changes (including anxiety), insomnia, 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 heartbeat, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), myocardial infarction.

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

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

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

From the side of metabolism and alimentary disorders: hyperglycemia.

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

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

On the part of the kidneys and urinary system: 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, asthenia, chest pain, pain, malaise.

Research: increase or decrease in body weight.

Exceptional cases of extrapyramidal syndrome have been reported.

Children. Amlodipine SAN tablets is well tolerated when used in children. The adverse reaction profile was similar to that observed in adults.

4 years.

Store in the original packaging at a temperature not higher than 25 °C.

Keep out of the reach of children.

10 tablets in a blister; 3 blisters in a pack.