Normodipine 10 mg No. 30 tablet.

Pharmacological properties of the drug Normodipin

Amlodipine (3-ethyl-5-methyl ester (±)-2-[aminomethoxy)methyl]-4-(o-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinecarboxylic acid) - ion antagonist calcium dihydropyridine group. By blocking slow calcium channels in the cell membrane, amlodipine inhibits the entry of calcium across the cell membrane into cardiomyocytes and vascular smooth muscle cells. Under its action, the tone of the smooth muscles of blood vessels (arterioles) decreases, the peripheral vascular resistance decreases, which leads to a decrease in blood pressure. For angina pectoris, the drug increases exercise tolerance, reduces the frequency of anginal attacks and the need for nitroglycerin. The antianginal effect of amlodipine is primarily due to the expansion of peripheral arterioles and a decrease in afterload on the heart. Considering that amlodipine does not cause reflex tachycardia, cardiac function and myocardial oxygen demand are reduced. Amlodipine dilates coronary vessels in both normal and ischemic areas, which improves myocardial perfusion and oxygen supply. In patients with hypertension (arterial hypertension), amlodipine, when taken once a day, significantly reduces blood pressure in the supine and standing position for 24 hours. The effect develops gradually and is not accompanied by the development of symptomatic hypotension. Amlodipine does not have a negative effect on metabolism, does not affect the lipid spectrum of the blood plasma, and can be used in patients with diabetes mellitus, gout, and also in patients with asthma. When taken orally, amlodipine is slowly and almost completely absorbed from the digestive tract. Eating does not affect the absorption of the drug. The concentration of amlodipine in the blood plasma reaches its maximum level 6–12 hours after administration. Bioavailability is 64–80%. The volume of distribution is about 20 l/kg body weight, 95–98% of amlodipine is bound to plasma proteins. In the liver, amlodipine is biotransformed to inactive metabolites. 10% of the drug is excreted unchanged in the urine, 60% in the form of inactive metabolites. Elimination is biphasic, the half-life averages 35–50 hours. The equilibrium state is achieved on the 7–8th day of continuous use of amlodipine. Features of pharmacokinetics allow the drug to be used once a day.

Normodipine 10 mg No. 30 tablet.

Instructions for medical use of the drug

Tradename

Normodipin®

International nonproprietary name

Amlodipine

Dosage form

Tablets 5 mg, 10 mg

Compound

One tablet contains the active substance - amlodipine 5 mg or 10 mg (in the form of amlodipine besylate 6.944 mg or 13.889 mg, respectively), excipients: magnesium stearate, sodium starch glycolate, type A, anhydrous calcium hydrogen phosphate, microcrystalline cellulose.

Description

The tablets are oblong-round in shape, with a biconvex surface, white or almost white, with “5” engraved on one side (for a dosage of 5 mg).

The tablets are oblong-round in shape, with a biconvex surface, white or almost white, with an engraving “10” on one side and a score line on the other (for a dosage of 10 mg).

Pharmacotherapeutic group

Drugs for the treatment of diseases of the cardiovascular system. Blockers of "slow" calcium channels. Blockers of “slow” calcium channels are selective. Dihydropyridine derivatives. Amlodipine. Code ATHS08CA01

Pharmacological properties

Pharmacokinetics

Absorption, distribution and binding to plasma proteins

Amlodipine is well absorbed after oral administration in therapeutic doses. The maximum concentration of the drug in the blood is observed after 6-12 hours. Absolute bioavailability is approximately 64-80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of amlodipine circulating in the blood is bound to plasma proteins.

Food intake does not affect the bioavailability of amlodipine.

Metabolism/Excretion

The terminal half-life is approximately 35-50 hours, allowing the drug to be administered once daily. Amlodipine is extensively metabolized in the liver to inactive metabolites, the drug is excreted in the urine in the form of the parent substance (10%) and metabolites (60%).

Use for liver dysfunction

There are limited clinical data regarding the use of amlodipine in patients with impaired liver function. Patients with hepatic impairment have reduced clearance of amlodipine, resulting in an increase in AUC of approximately 40-60% and prolongation of the half-life.

Use in elderly patients

The time to reach maximum plasma concentrations of amlodipine is similar in young and elderly patients. However, amlodipine clearance is reduced in elderly patients, resulting in increased AUC and half-life in the elderly. An increase in AUC and half-life has also been observed in patients with congestive heart failure.

Use in children and adolescents

A pharmacokinetic study was conducted in 74 children and adolescents aged 12 months to 17 years with arterial hypertension (34 patients aged 6 to 12 years, 28 patients aged 13 to 17 years). Patients received amlodipine in doses ranging from 1.25 to 20 mg once or twice daily. In children aged 6–12 years and adolescents aged 13–17 years, apparent clearance (CL/F) after oral administration was 22.5 and 27.4 L/h, respectively, in boys, and 16.4 and 21. 3 l/h, respectively - in girls. Large interindividual variability was observed. Data for children under 6 years of age are limited.

Pharmacodynamics

Being a dihydropyridine derivative, amlodipine inhibits the transmembrane transition of calcium ions (blocker of “slow” calcium channels or calcium ion antagonist); and also blocks the transmembrane flow of calcium ions into the smooth muscle cells of the myocardium and blood vessels.

The mechanism of the hypotensive effect of amlodipine is due to a direct relaxing effect on vascular smooth muscle. The exact mechanism of action of amlodipine in angina has not been fully established, but amlodipine reduces ischemia in the following two ways:

amlodipine dilates peripheral arterioles and, thus, reduces the total peripheral vascular resistance (afterload), which requires the work of the heart to overcome. Since the heart rate does not change, reducing the load on the heart reduces energy consumption and myocardial oxygen demand.
The mechanism of action of amlodipine probably also includes dilation of the main coronary arteries and coronary arterioles in both unchanged and ischemic areas of the myocardium. This dilation increases the supply of oxygen to the myocardium in patients with coronary artery spasm (Prinzmetal's angina or variant angina).

In patients with arterial hypertension, a single daily dose of amlodipine provides a clinically significant reduction in blood pressure over 24 hours, both in the supine and standing positions. Due to its slow onset of action, amlodipine does not cause acute arterial hypotension.

In patients with angina pectoris, a single daily dose of amlodipine increases the time of physical activity, delays the development of an angina attack and ST segment depression (by 1 mm) during exercise, reduces the frequency of angina attacks and the consumption of nitroglycerin tablets.

Amlodipine does not have a negative effect on metabolism and the lipid profile of blood plasma, so it can be used to treat patients with bronchial asthma, diabetes mellitus and gout.

Use in patients with coronary heart disease (CHD)

Data from clinical studies indicate that treatment with amlodipine is accompanied by a reduction in the frequency of hospitalizations due to angina pectoris and a reduction in the number of revascularization procedures in patients with coronary artery disease.

Use in patients with heart failure

Hemodynamic studies and controlled clinical studies using exercise testing have shown that amlodipine does not cause deterioration in patients with chronic heart failure (NYHA functional class II-IV), as evidenced by the degree of exercise tolerance, left ventricular ejection fraction and clinical symptoms.

Clinical data show that in patients with chronic heart failure of NYHA functional class III-IV without clinical symptoms or with objective symptoms indicating the presence of ischemic disease, with established therapy with ACE inhibitors, digitalis drugs and diuretics, amlodipine does not affect overall mortality.

Pediatric patients (6 years and older)

A study involving 268 children aged 6 to 17 years, predominantly suffering from secondary arterial hypertension, compared amlodipine at doses of 2.5 mg and 5 mg with placebo. The study demonstrated that both doses of the drug reduced systolic blood pressure to a significantly greater extent compared with placebo. The difference between the two doses was not statistically significant.

The long-term effects of amlodipine on growth, puberty and overall development have not been studied. The long-term effect of amlodipine therapy in childhood on reducing cardiovascular morbidity and mortality in adulthood has also not been established.

Indications for use

arterial hypertension. - chronic stable angina. - vasospastic angina (Prinzmetal's angina).

Directions for use and doses

Adults

Side effects

Often (≥1/100 and <1/10)

headache, dizziness, drowsiness (especially at the beginning of treatment)
cardiopalmus
"tides"
abdominal pain, nausea
swelling of ankles
swelling, fatigue

Uncommon(≥1/1,000 and <1/100)

insomnia, mood changes (including anxiety), depression, tremor, dysgeusia, syncope, hypoesthesia, paresthesia
visual impairment (including diplopia)
noise in ears
arterial hypotension
dyspnea, rhinitis
vomiting, dyspepsia, change in bowel habits (including diarrhea and constipation), dry mouth
alopecia, purpura, discoloration of the skin, hyperhidrosis, itching, rash, exanthema
arthralgia, myalgia, muscle cramps, back pain
urinary disorders, nocturia, frequent urination
impotence, gynecomastia
chest pain, asthenia, pain, malaise
weight gain, weight loss

Rarely(≥1/10000 and <1/1000)

confusion

Very rare(<1/10000)

leukocytopenia, thrombocytopenia
allergic reactions
hyperglycemia
muscle hypertonicity, peripheral neuropathy
myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)
vasculitis
cough
pancreatitis, gastritis, gingival hyperplasia, hepatitis, jaundice, increased activity of liver transaminases (mainly due to cholestasis)
angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity

Isolated cases of extrapyramidal syndrome have been reported.

Contraindications

hypersensitivity to amlodipine, dihydropyridine derivatives or any other components of the drug
severe arterial hypotension
shock (including cardiogenic shock)
left ventricular outflow tract obstruction (eg, severe aortic stenosis)
hemodynamically unstable heart failure after acute myocardial infarction
children up to 6 years old

Drug interactions

Effect of other drugs on Normodipin®

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 concentrations. Clinical manifestations of these pharmacokinetic abnormalities may be more pronounced in elderly patients. In this regard, monitoring of the clinical condition and dose adjustment may be required.

CYP3A4 inducers

There are no data regarding the effects of CYP3A4 inducers on amlodipine. Concomitant use of inducers of the CYP3A4 isoenzyme (for example, rifampicin, St. John's wort preparations) may lead to a decrease in the concentration of amlodipine in plasma. Caution should be exercised when administering amlodipine and CYP3A4 inducers simultaneously.

Concomitant use of amlodipine and consumption of grapefruits or grapefruit juice is not recommended as this may increase the bioavailability of amlodipine in some patients, which in turn may enhance the hypotensive effect.

Dantrolene (infusion)

In laboratory animals, cases of ventricular fibrillation and cardiovascular failure, accompanied by hyperkalemia, with death and collapse have been reported during the use of verapamil and intravenous administration of dantrolene. Due to the risk of hyperkalemia, the simultaneous use of dantrolene and slow calcium channel blockers, including amlodipine, should be avoided in patients susceptible to malignant hyperthermia, as well as during the treatment of malignant hyperthermia.

Normodipine® enhances the hypotensive effect of other drugs that have antihypertensive effects and are used to lower blood pressure.

In clinical drug interaction studies, amlodipine had no effect on the pharmacokinetics of atorvastatin, digoxin, warfarin or cyclosporine.

Simvastatin

Simultaneous repeated use of amlodipine at a dose of 10 mg with simvastatin at a dose of 80 mg led to an increase in simvastatin concentrations by 77% compared with simvastatin monotherapy. It is recommended to limit the dose of simvastatin in patients taking amlodipine to 20 mg per day.

special instructions

The safety and effectiveness of Normodipin® in hypertensive crisis has not been established. Patients with heart failure In long-term, placebo-controlled clinical trials in patients with heart failure (NYHA functional class III-IV), it was found that the incidence of pulmonary edema increased in the group receiving amlodipine compared with the placebo group. . Slow calcium channel blockers, including amlodipine, should be used with caution in the treatment of patients with congestive heart failure, as they increase the risk of cardiovascular complications and the percentage of deaths. Use in patients with impaired liver function In patients with impaired liver function, the half-life of amlodipine and AUC values are increased; recommended doses for such patients have not been established. Treatment with amlodipine should begin with minimal doses, and caution should be used during initial treatment and when increasing the dose. In patients with severe hepatic impairment, dose titration should be carried out under close medical supervision. Use in elderly patients Dose increases in elderly patients should be carried out with caution. Use in patients with impaired renal function In this group of patients, amlodipine can be used in normal doses. Changes in plasma concentrations of amlodipine do not correlate with the degree of renal dysfunction. Amlodipine is not eliminated by hemodialysis.

Pregnancy and lactation

The safety of the drug during pregnancy and lactation has not been established. Use during pregnancy is recommended only if a safer alternative is not available or if the maternal illness poses a greater danger to the mother and fetus than treatment.

It is not known whether amlodipine passes into breast milk. The decision to continue/discontinue breastfeeding or to continue/discontinue treatment with amlodipine should be made taking into account the benefits of breastfeeding for the child and the benefit received by the mother from treatment.

Features of the effect of the drug on the ability to drive a vehicle or potentially dangerous mechanisms

Amlodipine may have some effect on the ability to drive a car and use machinery. If a patient taking amlodipine experiences dizziness, headache, fatigue or nausea, this may affect the speed and quality of the response. Caution is recommended during the initial phase of treatment.

Overdose

Experience in the treatment of intentional drug overdose in humans is limited.

Symptoms: excessive peripheral vasodilation, with the possible development of reflex tachycardia. Cases of severe and persistent arterial hypotension, including the development of shock and death, have been described. Treatment: carrying out active measures aimed at maintaining the function of the cardiovascular system, including bringing the lower extremities into an elevated position, monitoring heart and lung performance, monitoring circulating blood volume and diuresis.

To restore vascular tone and normalize blood pressure, in the absence of contraindications, it is possible to use vasoconstrictor drugs. To eliminate the effects of calcium channel blockade, calcium gluconate is administered intravenously.

In some cases, gastric lavage may be effective. Administration of activated charcoal to healthy volunteers immediately or within 2 hours after taking amlodipine at a dose of 10 mg led to a significant decrease in drug absorption. Since amlodipine is largely bound to serum proteins, hemodialysis is ineffective.

Release form and packaging

10 tablets are placed in a blister pack made of polyvinyl chloride film and aluminum foil.

3 blister packs together with instructions for medical use in the state and Russian languages are placed in a cardboard box.

Storage conditions

Store at temperatures between 15°C and 30°C. Keep out of the reach of children!

Shelf life

3 years. Do not use after expiration date.

Conditions for dispensing from pharmacies

On prescription.

Side effects of the drug Normodipin

Headache, swelling, increased fatigue, drowsiness, nausea, abdominal pain, flushing of the facial skin, tachycardia and dizziness are noted. Rarely - intestinal dysfunction, arthralgia, asthenia, shortness of breath, dyspepsia, gingival hyperplasia, gynecomastia, impotence, frequent urination, mood lability, myalgia, itchy skin, rash, blurred vision. Extremely rarely - polymorphic erythema, jaundice, changes in the activity of liver enzymes, caused in most cases by cholestasis.

Norodent

wax briquette for killing rats and mice

Ready-to-use food bait in the form of a paraffin-containing red briquette. Contains the active ingredient brodifacoum in an amount of 0.005%, as well as an attractant, antioxidant, red dye, food base and bitrex (bitter component), which protects the bait from being eaten by domestic animals.

The product has high rodenticidal activity for rats and mice: their death occurs after 4-10 days, although they receive a lethal dose within 1-2 days.

Briquettes, whole or broken into pieces, are placed in previously identified rodent habitats: along walls, partitions, near burrows, laid out in dry places under shelters (cabinets, equipment, etc.) in adapted containers (bait boxes, drainage pipes, trays, boxes) or in special containers. The latter are preferable because they increase the palatability of the product, preventing it from being taken away by rodents, and also complicate access to the bait for non-target animal species. To kill rats, briquettes are laid out in 3-5 pieces in a room, for mice - 1-2 briquettes.

soft briquette for killing rats and mice

Composition brodifacoum – 0.005%; bitrex, dye, food base.

granules for the destruction of gray and black rats, house and field mice, water rats

Red granules containing 0.005% bromadiolone as an active ingredient, as well as a red dye, food base and bitrex (bitter component), which protects the bait from being eaten by birds and reduces the risk of accidental poisoning of people and non-target animal species. The product has high rodenticidal activity for gray, black and water rats, mice and moles: death of gray rats occurs after 4-14 days (6.4 on average), water rats - after 5-7 days (6.5 on average), mice - after 4-9 days (6.2 on average), although they received a lethal dose within 1-2 days. The death of moles is evidenced by unopened molehills and the absence of fresh soil emissions. The bait is placed in places where traces of rodent activity (gnaws, droppings) are found: on travel routes, along walls, partitions, near burrows. Place the bait in dry places under shelters (cabinets, equipment, etc.) in adapted containers (bait boxes, drainage pipes, trays, boxes, etc.) or in special containers. The latter is preferable, because increase the palatability of the product, preventing it from being taken away by rodents, and also complicate access to the bait for non-target animal species.

The bait is laid out in 30-50 g doses for treatments against rats and 10-20 g for mice. To fight moles, you need to make a vertical cut in the molehill between two outbursts of earth and put 15-20 g of bait at both ends. Then cover the cutout with a plank and cover it with earth. You can put a waterproof pipe with a diameter of at least 5 cm in the cutout so that the mole can move freely, and put bait in it, also covering it with earth. The check is carried out after 2-3 days.

grain bait for killing rats and mice

Ready-to-use red food bait. Contains bromadiolone as an active ingredient (AI) - 0.005%, as well as bitrex (bitter component), which protects baits from being eaten by birds and reduces the risk of accidental poisoning of people and non-target animal species, dye, triethylene glycol and food fillers. The product is intended for the destruction of rats (gray, black, water) and mice on objects of various categories. The product has high rodenticidal activity for rats and mice: the ingestibility of the bait is: 35.9% of the daily diet of rats and 51.9% of mice. The death of rats and mice was 100% and occurred on days 5-8 (6.3 days on average) in rats and on days 4-8 (7.0 days on average) in mice. The bait is placed in places where traces of rodent activity (gnaws, droppings) are found: on travel routes, along walls, partitions, near burrows. Place the bait in dry places under shelters (cabinets, equipment, etc.) in adapted containers (bait boxes, drainage pipes, trays, boxes, etc.) or in special containers. The latter is preferable, because increases the palatability of the product, preventing it from being taken away by rodents, and also complicates access to the bait for non-target animal species. The bait is laid out in 30-50 g doses for treatments against rats and 10-20 g for mice. If this amount of bait is eaten, then it turns out to be enough to kill the rodents, since bromadiolone, unlike other analogues, not only has an anticoagulant effect, but also exhibits the properties of an acute poison. Bait for water rats (voles) is laid out in 15-30 g quantities in underground structures where this species can penetrate.

Precautionary measures

Use and store out of the reach of children and animals. Wear gloves, do not smoke, do not drink. The packaging and remains of the bait are burned or buried. After work, wash your hands with soap and water. If it gets into the stomach, immediately (no later than 30 minutes) induce vomiting and consult a doctor. The antidote is vitamin K1 or K3. Before the doctor's examination, do not eat, drink 3-4 glasses of water with 10-12 tablets. activated carbon.

Storage conditions and periods

Store in a dry, covered warehouse in a closed container at a temperature from -10 °C to +30 °C, separately from feed and forage. Guaranteed shelf life 2 years.

Release form

Available in polyethylene packages of 200 g and buckets of 10 kg.

Manufacturer

LLC “Vashe Khozyaystvo”, Russia. Made to order of LLC “Trading House VIK”, Russia

Special instructions for the use of the drug Normodipin

During pregnancy and breastfeeding, the use of Normodipin is possible only for absolute indications. In this case, it is necessary to evaluate the benefit/risk ratio, since the safety of using Normodipine during pregnancy and lactation has not been established. In elderly patients, there was a tendency to decrease the clearance of amlodipine, which leads to an increase in AUC and half-life. In heart failure, the increase in AUC and half-life corresponds to the age group. For elderly people and patients with heart failure, the drug is prescribed in normal doses. In patients with impaired liver function, the half-life of amlodipine increases. Recommendations regarding dosing of the drug in this case have not been developed, so the drug should be used with caution in these patients. In patients with renal failure, Normodipine is used in normal doses. Changes in amlodipine plasma concentrations do not correlate with the degree of renal dysfunction. Amlodipine is not excreted during dialysis. Amlodipine does not cause deterioration in the condition of patients with heart failure (functional class II–IV according to the NYHA classification) according to such criteria as exercise tolerance, left ventricular ejection fraction and clinical symptoms. The question of the patient’s ability to drive vehicles and operate machinery during treatment with Normodipine is decided individually, depending on the patient’s response to the drug.

Instructions for use NORMODIPINE®

As a dihydropyridine derivative, amlodipine inhibits the transmembrane transition of calcium ions into vascular smooth muscle cells and cardiomyocytes.

The mechanism of the hypotensive effect of amlodipine is due to a direct relaxing effect on vascular smooth muscle.

The exact mechanism of action of amlodipine in angina pectoris has not been fully established, but the antianginal effect of amlodipine is due to the following:

amlodipine dilates peripheral arterioles and, thus, reduces peripheral vascular resistance (afterload), which requires the work of the heart to overcome. Since heart rate does not change, reducing the load on the heart reduces energy consumption and myocardial oxygen demand;
The mechanism of action of amlodipine also likely involves dilatation of the main coronary arteries and coronary arterioles in both normal and ischemic areas of the myocardium, thereby increasing the supply of oxygen to the myocardium in patients with coronary artery spasm (Prinzmetal's angina or variant angina).

In patients with arterial hypertension, a single daily dose of amlodipine provides a clinically significant reduction in blood pressure over 24 hours, both in the supine and standing positions. Due to the gradual action of amlodipine, acute orthostatic hypotension is rarely observed.

In patients with angina pectoris, a single daily dose of amlodipine increases the time it takes to perform physical activity, delays the development of an angina attack and ST segment depression (1 mm below the isoline) during exercise, reduces the frequency of angina attacks and the consumption of nitroglycerin tablets.

Amlodipine does not have a negative effect on metabolism and the lipid profile of blood plasma, so it can be used to treat patients with bronchial asthma, diabetes mellitus and gout.

Use in patients with coronary artery disease

The effectiveness of amlodipine for the prevention of clinical events in patients with coronary artery disease was studied in an independent multicenter, randomized, double-blind, placebo-controlled study, CAMELOT (Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis), which included 1997 patients. . In this study, 663 patients received amlodipine at a dose of 5-10 mg for 2 years, 673 patients received enalapril at a dose of 10-20 mg and 655 patients received placebo in combination with standard therapy, including statins, beta-blockers, diuretics and aspirin. The main efficacy results are presented in Table 1. The study results indicate that treatment with amlodipine was associated with a decrease in the incidence of hospitalization due to angina pectoris and a decrease in the number of revascularization procedures in patients with coronary artery disease.

Table 1. Frequency of significant clinical outcomes in the CAMELOT study

Cardiovascular complications, number (%)				Amlodipine vs Placebo
Clinical outcome	Amlodipine	Placebo	Enalapril	Risk ratio (95% CI)	P value
Primary endpoint
Adverse cardiovascular events	110 (16.6)	151 (23.1)	136 (20.2)	0.69 (0.54-0.88)	0.003
Individual components
Coronary artery revascularization	78 (11.8)	103 (15.7)	95 (14.1)	0.73 (0.54-0.98)	0.03
Hospitalization due to angina pectoris	51 (7.7)	84 (12.8)	86 (12.8)	0.58 (0.41-0.82)	0.002
Non-fatal MI	14 (2.1)	19 (2.9)	11 (1.6)	0.73 (0.37-1.46)	0.37
Stroke or TIA	6 (0.9)	12 (1.8)	8 (1.2)	0.50 (0.19-1.32)	0.15
Death due to cardiovascular pathology	5 (0.8)	2 (0.3)	5 (0.7)	2.46 (0.48-12.7)	0.27
Hospitalization due to CHF	3 (0.5)	5 (0.8)	4 (0.6)	0.59 (0.14-2.47)	0.46
Resuscitation after cardiac arrest	0	4 (0.6)	1 (0.1)	N.A.	0.04
Newly diagnosed peripheral blood vessel disease	5 (0.8)	2 (0.3)	8 (1.2)	2.6 (0.50-13.4)	0.24

Abbreviations: CHF—congestive heart failure, CI—confidence interval, MI—myocardial infarction, TIA—transient ischemic attack.

Use in patients with heart failure

In a placebo-controlled study (PRAISE) in patients with NYHA class III-IV heart failure treated with digoxin, diuretics, and ACE inhibitors, amlodipine did not increase the risk of death or the total risk of mortality and complications associated with heart failure. .

In an additional placebo-controlled study (PRAISE-2) in patients with chronic heart failure (NYHA functional class III-IV) without clinical or objective signs of coronary artery disease, who were constantly receiving ACE inhibitors, digitalis and diuretics, amlodipine had no effect on general and cardiovascular health. mortality. In the same patients, the use of amlodipine was accompanied by an increase in the incidence of pulmonary edema.

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

A randomized, double-blind morbidity and mortality study called the Antihypertensive and Lipid-Lowering Treatment to Prevent Myocardial Infarction Trial (ALLHAT) was conducted to compare the effects of newer drugs such as amlodipine at a dose of 2.5-10 mg/day (calcium channel blocker). or lisinopril at a dose of 10-40 mg/day (ACE inhibitor) as first-line drugs with the action of the thiazide diuretic chlorthalidone, at a dose of 12.5-25 mg/day for the treatment of mild to moderate arterial hypertension.

A total of 33,357 patients with hypertension aged 55 years and older were randomized and followed for an average of 4.9 years. Patients had at least one additional risk factor for coronary artery disease, including previous myocardial infarction or stroke (>6 months before enrollment); documented other cardiovascular disease of atherosclerotic origin (total 51.5%); type 2 diabetes mellitus (36.1%); HDL-C <35 mg/dL (11.6%); left ventricular hypertrophy diagnosed by ECG or echocardiography (20.9%); smoking (21.9%).

The primary endpoint was a composite of fatal CAD or nonfatal myocardial infarction. There was no significant difference in the incidence of the primary endpoint between amlodipine and chlorthalidone therapy: RR 0.98 95% CI [0.90-1.07] p=0.65. Among secondary endpoints, heart failure (component of the composite cardiovascular endpoint) was significantly higher in the amlodipine group than in the chlorthalidone group (10.2% vs 7.7%, RR 1.38, 95% CI [1.25-1.52] p<0.001). However, there was no significant difference in all-cause mortality between amlodipine and chlorthalidone therapy:

RR 0.96 95% CI [0.89-1.02] p=0.20.

Pediatric patients (6 years and older)

A study involving 268 children aged 6 to 17 years, predominantly suffering from secondary hypertension, compared amlodipine at doses of 2.5 mg and 5 mg with placebo. The study demonstrated that both doses of the drug reduced systolic blood pressure to a significantly greater extent compared with placebo. The difference between the two doses was not statistically significant.

The long-term effects of amlodipine on growth, puberty and overall development have not been studied.

The long-term effect of amlodipine therapy in childhood on reducing cardiovascular morbidity and mortality in adulthood has also not been established.

Drug interactions Normodipin

Normodipine can be safely used with thiazide diuretics, beta-adrenergic blockers, ACE inhibitors, nitrates, NSAIDs, antibiotics, and oral hypoglycemic agents. The simultaneous use of Normodipine and digoxin in healthy volunteers did not change the level of digoxin in the blood serum and its clearance. Concomitant use of cimetidine does not change the pharmacokinetics of amlodipine. Normodipine does not affect the protein binding of digoxin, phenytoin, coumarin, and indomethacin. In healthy male volunteers, simultaneous use of Normodipine with warfarin did not have a significant effect on prothrombin time. Normodipine does not affect the pharmacokinetics of cyclosporine.

Normodipine®

Contraindicated drug combinations

Dantrolene (intravenous administration)

In laboratory animals, cases of ventricular fibrillation with death and collapse were observed during the use of verapamil and intravenous dantrolene, accompanied by hyperkalemia. Due to the risk of developing hyperkalemia, simultaneous use of Normodipin® containing amlodipine, a blocker of “slow” calcium channels, should be avoided in patients susceptible to malignant hyperthermia, as well as during the treatment of malignant hyperthermia.

Not recommended drug combinations

Grapefruit juice

Taking amlodipine with grapefruit or grapefruit juice is not recommended as the bioavailability of amlodipine may be increased in some patients, resulting in increased blood pressure lowering effects.

Combinations of drugs that require special caution when used

Inducers of the
CYP3A4 isoenzyme There pharmacokinetics
of amlodipine. Concomitant use of inducers of the CYP3A4 isoenzyme (for example, rifampicin, St. John's wort ( Hypericum perforatum)

)) and amlodipine may lead to a decrease in plasma concentrations of amlodipine. Caution should be exercised when using the drug Normodipin simultaneously with inducers of the CYP3A4 isoenzyme.

Inhibitors of the
CYP 3 A 4
isoenzyme Concomitant use of amlodipine and strong or moderate CYP3A4 inhibitors (protease inhibitors, for example, ritonavir, azole antifungals, macrolides, for example, erythromycin or clarithromycin, verapamil or diltiazem) can lead to a significant increase in the concentration of amlodipine. Clinical manifestations of these pharmacokinetic abnormalities may be more pronounced in elderly patients. In this regard, monitoring of the clinical condition and dose adjustment of Normodipin® may be required.

Combinations of drugs that require caution when used

Simvastatin

Repeated administration of amlodipine at a dose of 10 mg in combination with simvastatin at a dose of 80 mg resulted in an increase in simvastatin exposure by 77% compared with simvastatin monotherapy. Therefore, patients receiving amlodipine should take simvastatin at a daily dose of no more than 20 mg.

Calcium preparations

May reduce the effect of BMCC.

Lithium preparations

When BMCC is used together with lithium preparations (no data are available for amlodipine), their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor or tinnitus) may increase.

Baclofen

Strengthening the antihypertensive effect. Blood pressure and renal function should be monitored, and the dose of amlodipine should be adjusted if necessary.

Amifostin

The antihypertensive effect of amlodipine may be enhanced.

Glucocorticosteroids

Decreased antihypertensive effect (retention of fluid and sodium ions as a result of the action of corticosteroids).

Tricyclic antidepressants, antipsychotics, isoflurane

There is an increased risk of orthostatic hypotension and increased antihypertensive effect (additive effect).

Tacrolimus

When used simultaneously with amlodipine, there is a risk of increasing the concentration of tacrolimus in the blood plasma. To avoid toxicity of tacrolimus when used concomitantly with amlodipine, the concentration of tacrolimus in the blood plasma of patients should be monitored and the dose of tacrolimus should be adjusted if necessary.

Tasonermin

When used concomitantly, amlodipine may increase the systemic exposure of tasonermin

in blood plasma. In such cases, regular monitoring of tasonermin in the blood and dose adjustment if necessary is necessary.

mTOR inhibitors ( mammalian Target of Rapamycin )
mTOR inhibitors such as sirolimus, temsirolimus and everolimus are substrates of the CYP3A isoenzyme. Amlodipine is a weak inhibitor of the CYP3A isoenzyme. When used concomitantly with mTOR inhibitors, amlodipine may increase their exposure.

Other interactions with amlodipine

For the treatment of arterial hypertension, amlodipine can be safely used with thiazide diuretics, alpha-blockers, beta-blockers and ACE inhibitors.

In patients with stable angina, simultaneous use of amlodipine with other antianginal drugs, such as

long- and short-acting
nitrates beta-blockers, is possible.
It is possible that the antianginal and antihypertensive effects of BMCC may be enhanced when used simultaneously with thiazide and loop diuretics, ACE inhibitors, beta-blockers and nitrates, as well as their antihypertensive effect is enhanced when prescribed with alpha1-blockers and antipsychotics.

Amlodipine does not cause a negative inotropic effect. However, some CBMCs may increase the negative inotropic effect of antiarrhythmic drugs that cause QT prolongation (eg, amiodarone and quinidine).

Unlike other BMKK. no significant interaction was detected between amlodipine (3rd generation BMCC) and NSAIDs,

including
indomethacin
.

It is safe to administer amlodipine with oral hypoglycemic agents.

Single dose of sildenafil

at a dose of 100 mg in patients with essential arterial hypertension had no effect on the pharmacokinetics of amlodipine.

Combined multiple doses of amlodipine 10 mg and atorvastatin

at a dose of 80 mg led to an insignificant change in the pharmacokinetic parameters of atorvastatin at steady state.

Ethanol (beverages containing alcohol):

amlodipine does not have a significant effect on the pharmacokinetics of ethanol with single or repeated use at a dose of 10 mg.

Cyclosporine interaction studies

and amlodipine in healthy volunteers and in special groups of patients have not been conducted, with the exception of patients after kidney transplantation. Various studies of the interaction of amlodipine with cyclosporine in patients after kidney transplantation show that the use of this combination may either not lead to any effect or increase the minimum concentration of cyclosporine to varying degrees, up to 40%. Cyclosporine concentrations should be monitored in patients after kidney transplantation.

With simultaneous use of amlodipine and digoxin

renal clearance and serum digoxin concentrations do not change.

With simultaneous use of warfarin

with amlodipine, prothrombin time does not change.

When used simultaneously with cimetidine

the pharmacokinetics of amlodipine does not change.

Amlodipine does not affect the degree of binding of digoxin, phenytoin, warfarin

and
indomethacin
with blood plasma proteins
in vitro .
Aluminum and magnesium-containing antacids:

a single dose of such antacids together with amlodipine does not have a significant effect on the pharmacokinetics of amlodipine.

Overdose of the drug Normodipin, symptoms and treatment

Data is limited. Given the slow absorption of the drug, it is advisable to rinse the stomach. A significant overdose can lead to pronounced peripheral vasodilation with a significant and prolonged decrease in blood pressure. Clinically significant arterial hypotension caused by an overdose of amlodipine requires urgent measures aimed at maintaining the function of the cardiovascular and respiratory systems, including monitoring vital signs, elevated position of the lower extremities, replenishment of blood volume and diuresis control, and, if necessary, symptomatic treatment. To restore vascular tone and increase blood pressure, vasoconstrictor drugs can be used if there are no contraindications to their use. To eliminate the blockade of calcium channels, intravenous administration of calcium gluconate is indicated. Since amlodipine is highly bound to plasma proteins, dialysis is ineffective.

Normodipine 10 mg 30 pcs. pills

pharmachologic effect

Antianginal, hypotensive.

Composition and release form Normodipin 10 mg 30 pcs. pills

Tablets - 1 tablet:

active substance: amlodipine - 5/10 mg (in the form of 6.944/13.889 mg amlodipine besylate, respectively);
excipients: magnesium stearate - 2/4 mg; sodium carboxymethyl starch - 4/8 mg; calcium hydrogen phosphate anhydrous - 63/126 mg; MCC - 124.056/284.111 mg.

Tablets, 5 mg and 10 mg. In a blister of aluminum/PVC, 10 pcs. 3 blisters in a cardboard box.

Description of the dosage form

The tablets are white or almost white, biconvex, oblong-round in shape, with “5” engraved on one side.

Characteristic

Calcium antagonist from the dihydropyridine group.

Directions for use and doses

Orally, the initial dose for the treatment of arterial hypertension and angina pectoris is 5 mg/day. The maximum daily dose is 10 mg once. For arterial hypertension, the maintenance dose can be 5 mg/day (1 tablet of 5 mg).

In elderly patients, T1/2 of amlodipine may increase and creatinine clearance may decrease. No dose changes are required, but patients should be monitored more closely.

No dose change is required when administered concomitantly with thiazide diuretics, β-blockers and ACE inhibitors.

No dose adjustment is required in patients with renal impairment.

Pharmacodynamics

A slow calcium channel blocker, a dihydropyridine derivative, has antianginal and hypotensive effects. By binding to the S6 segments of the III and IV domains of the alpha1 subunit of the L-type calcium channel, it blocks calcium channels, reduces the transmembrane transition of calcium ions into the cell (more into vascular smooth muscle cells than into cardiomyocytes). The antianginal effect is due to the expansion of the coronary and peripheral arteries and arterioles: in case of angina pectoris, it reduces the severity of myocardial ischemia; by expanding peripheral arterioles, it reduces peripheral vascular resistance, reduces preload on the heart, and reduces myocardial oxygen demand. Expands coronary arteries and arterioles in unchanged and ischemic areas of the myocardium, increases the supply of oxygen to the myocardium (especially with vasospastic angina); prevents the development of spasm of the coronary arteries (including those caused by smoking). In patients with stable angina, a single daily dose increases exercise tolerance, slows down the development of angina and “ischemic” depression of the ST segment, reduces the frequency of angina attacks and the consumption of nitroglycerin and other nitrates.

It has a long-term dose-dependent hypotensive effect. The hypotensive effect is due to a direct vasodilating effect on vascular smooth muscle. For arterial hypertension, a single dose provides a clinically significant reduction in blood pressure over 24 hours (in the patient’s “lying” and “standing” position).

Orthostatic hypotension when prescribing amlodipine is quite rare. Does not cause a decrease in exercise tolerance or left ventricular ejection fraction. Reduces the degree of left ventricular myocardial hypertrophy. It has no effect on myocardial contractility and conductivity, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases the glomerular filtration rate, and has a weak natriuretic effect. In diabetic nephropathy, it does not increase the severity of microalbuminuria. It does not have any adverse effect on metabolism and plasma lipid concentrations and can be used in the treatment of patients with bronchial asthma, diabetes mellitus and gout.

The onset of the effect is 2-4 hours, the duration of the effect is 24 hours.

Pharmacokinetics

Suction

When taken orally, it is slowly and almost completely absorbed from the gastrointestinal tract. Eating does not affect absorption. Cmax in blood plasma is achieved after 6-9 hours in both elderly and young patients. The average absolute bioavailability is 64%.

Distribution

Css of amlodipine in blood plasma is achieved after continuous use for 7-8 days.

Vd is approximately 21 l/kg, indicating predominant tissue distribution. Penetrates through the blood-brain barrier and into breast milk.

Plasma protein binding - 97%.

Metabolism

About 90% of amlodipine is biotransformed in the liver with the formation of inactive metabolites.

Removal

Amlodipine is excreted from the body in the urine (10% of the dose unchanged and 60% in the form of inactive metabolites) and in feces (20-25% in the form of metabolites). Elimination is biphasic, T1/2 averages 31-48 hours. The total clearance of amlodiline is 7 ml/min/kg. Hemodialysis does not remove amlodipine.

Pharmacokinetics in special clinical situations

In elderly patients (over 65 years of age), the elimination of amlodipine is slower (T1/2 - 65 hours) compared to young patients, but these differences are not clinically significant.

Prolongation of T1/2 in patients with liver failure suggests that with long-term administration, the accumulation of the drug in the body will be higher (T1/2 - up to 60 hours).

The presence of renal failure in the patient does not significantly affect the pharmacokinetics of amlodipine.

Indications for use Normodipin 10 mg 30 pcs. pills

arterial hypertension (as monotherapy or in combination with other antihypertensive drugs);
stable angina pectoris (as monotherapy or in combination with other antianginal drugs);
vasospastic angina (Prinzmetal's angina) (as monotherapy or in combination with other antianginal drugs).

Contraindications

severe arterial hypotension (systolic blood pressure less than 90 mm Hg);
collapse;
cardiogenic shock;
clinically significant aortic stenosis;
unstable angina (with the exception of Prinzmetal angina);
pregnancy;
lactation period;
age under 18 years (due to lack of clinical experience in use);
hypersensitivity to amlodipine and other dihydropyridine derivatives.

The drug should be prescribed with caution in case of liver dysfunction, SSSS (severe bradycardia, tachycardia), chronic heart failure of non-ischemic etiology of functional class III-IV according to the NYHA classification, arterial hypotension, mitral stenosis, hypertrophic obstructive cardiomyopathy, acute myocardial infarction (and within 1 months after it), elderly patients.

Application of Normodipin 10 mg 30 pcs. pills during pregnancy and breastfeeding

Animal studies have not revealed the teratogenic effect of amlodipine, but there is no clinical experience with its use during pregnancy and lactation. Therefore, amlodipine should not be prescribed to pregnant and lactating women, or women of childbearing potential unless they are using reliable methods of contraception.

Contraindicated in children and adolescents under 18 years of age.

special instructions

During treatment with Normodipin®, it is necessary to monitor body weight and sodium intake, and prescribing an appropriate diet is indicated. It is necessary to maintain dental hygiene and follow-up with a dentist (to prevent pain, bleeding and gum hyperplasia).

Patients with low body weight, patients of short stature and patients with severe liver dysfunction may require a lower dose.

If liver function is impaired, T1/2 of the drug may also be prolonged. Therefore, Normodipin® should be prescribed to such patients with caution.

Despite the fact that discontinuation of the drug Normodipin® is not accompanied by the development of withdrawal syndrome, it is advisable to discontinue treatment by gradually reducing the dose of the drug.

The effectiveness and safety of the drug in hypertensive crisis have not been established.

Impact on the ability to drive vehicles and operate machinery

There have been no reports of the effect of Normodipine® on driving or operating machinery. However, some patients, mainly at the beginning of treatment, may experience drowsiness, dizziness and other side effects from the nervous system. If they occur, the patient must take special precautions when driving a car and working with complex mechanisms.

Overdose

Symptoms: marked decrease in blood pressure, tachycardia, excessive peripheral vasodilation (risk of developing severe and persistent arterial hypotension, including with the development of shock and death).

Treatment: gastric lavage, administration of activated charcoal, maintaining the function of the cardiovascular system, monitoring indicators of heart and lung function, elevated, above head level, position of the lower extremities, control of blood volume and diuresis. To restore vascular tone, use vasoconstrictors (in the absence of contraindications to their use); in order to eliminate the consequences of blockade of calcium channels - intravenous administration of calcium gluconate. Hemodialysis is ineffective.

Side effects Normodipin 10 mg 30 pcs. pills

The frequency of adverse reactions is presented in accordance with the following gradation: very often (≥1/10), often (≥1/100,

From the cardiovascular system: often - palpitations, peripheral edema (swelling of the ankles and feet), flushing of the facial skin; infrequently - excessive decrease in blood pressure; very rarely - development or worsening of heart failure, rhythm disturbances (bradycardia, ventricular tachycardia, atrial fibrillation), myocardial infarction, chest pain, orthostatic hypotension, vasculitis.

From the central and peripheral nervous system: often - headache, dizziness, increased fatigue, drowsiness; uncommon - asthenia, general malaise, hypoesthesia, paresthesia, peripheral neuropathy, tremor, vertigo, fainting, insomnia, mood lability, unusual dreams, increased excitability, depression, anxiety; very rarely - apathy, ataxia, agitation, amnesia.

From the digestive system: often - nausea, abdominal pain; sometimes - vomiting, constipation or diarrhea, flatulence, dyspepsia, anorexia, dry mouth, thirst; rarely - gum hyperplasia, increased appetite; very rarely - pancreatitis, gastritis, jaundice (due to cholestasis), hyperbilirubinemia, increased activity of liver transaminases, hepatitis.

From the hematopoietic organs: very rarely - thrombocytopenic purpura, leukopenia, thrombocytopenia.

From the genitourinary system: rarely - frequent urination, painful urination, nocturia, impotence; very rarely - dysuria, polyuria.

From the skin: rarely - dermatitis; very rarely - purpura, xeroderma, skin pigmentation disorder.

Allergic reactions: infrequently - skin itching, rash (including erythematous, maculopapular rash); very rarely - urticaria, angioedema, erythema multiforme.

From the musculoskeletal system: sometimes - muscle cramps, myalgia (with long-term use), arthralgia, back pain, arthrosis; rarely - myasthenia.

From the senses: rarely - visual impairment, diplopia, conjunctivitis, eye pain, xerophthalmia, tinnitus.

Other: rarely - alopecia, gynecomastia, hyperuricemia, weight gain/loss, dyspnea, nosebleeds, increased sweating; very rarely - cold sticky sweat, cough, rhinitis, parosmia, impaired taste, impaired accommodation, hyperglycemia.

Drug interactions

Amlodipine can be safely used for the treatment of hypertension together with thiazide diuretics, alpha-blockers, beta-blockers or ACE inhibitors. In patients with stable angina, the drug can be combined with other antianginal agents, for example, long-acting nitrates, beta-blockers or short-acting nitrates.

Amlodipine can be used simultaneously with NSAIDs (especially indomethacin), antibacterial agents and oral hypoglycemic agents.

It is possible to enhance the antianginal and hypotensive effect of slow calcium channel blockers of the dihydropyridine series when used together with thiazide and loop diuretics, verapamil, ACE inhibitors, beta-blockers and nitrates, as well as enhance their hypotensive effect when used together with alpha1-blockers, antipsychotics .

Although negative inotropic effects have not generally been observed in amlodipine studies, some calcium channel blockers may enhance the negative inotropic effects of antiarrhythmic drugs that cause QT prolongation (eg, amiodarone and quinidine).

A single dose of sildenafil in a dose of 100 mg in patients with essential hypertension does not affect the pharmacokinetic parameters of amlodipine.

Repeated use of amlodipine at a dose of 10 mg and atorvastatin at a dose of 80 mg is not accompanied by significant changes in the pharmacokinetics of atorvastatin.

Amlodipine with single and repeated use in a dose of 10 mg does not affect the pharmacokinetics of ethanol (drinks containing alcohol).

Antiviral agents (ritonavir) increase plasma concentrations of slow calcium channel blockers, incl. amlodipine.

Neuroleptics and isoflurane enhance the hypotensive effect of dihydropyridine derivatives.

Calcium supplements may reduce the effect of slow calcium channel blockers.

When amlodipine is used together with lithium preparations, it is possible to increase the manifestation of neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

Amlodipine does not change the pharmacokinetics of cyclosporine.

Does not affect the serum concentration of digoxin and its renal clearance.

Does not have a significant effect on the effect of warfarin (prothrombin time).

Cimetidine does not affect the pharmacokinetics of amlodipine.

In in vitro studies, amlodipine does not affect the binding of digoxin, phenytoin, warfarin and indomethacin to blood proteins.

A simultaneous single dose of 240 mg of grapefruit juice and 10 mg of amlodipine orally is not accompanied by a significant change in the pharmacokinetics of amlodipine.