Norvasc, tablets 5 mg 30 pcs

Norvasc – antihypertensive, antianginal.

Pharmacodynamics

Dihydropyridine derivative – BKK of III generation, has hypotensive and antianginal effect. It blocks slow calcium channels, reduces transmembrane transfer of calcium ions into the cell (more so into vascular smooth muscle cells than into cardiomyocytes).

The antianginal action is due to the dilation of coronary and peripheral arteries and arterioles:

In angina, it reduces the severity of myocardial ischemia; by dilating the peripheral arterioles, it reduces the RPS, reduces the afterload on the heart, and reduces myocardial oxygen demand;

– By dilating coronary arteries and arterioles in unchanged and ischemic areas of the myocardium, increases the flow of oxygen to the myocardium (especially in vasospastic angina); prevents coronary artery spasm (including that caused by smoking).Also caused by smoking).

In patients with stable angina a single daily dose increases exercise tolerance, slows the development of angina attacks and ischemic ST-segment depression, reduces the frequency of angina attacks and 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 the vascular smooth muscles. In case of arterial hypertension a single dose provides clinically significant BP reduction during 24 hours (in a patient lying and standing position).

Orthostatic hypotension with amlodipine is rare. Amlodipine does not cause decreased tolerance to physical load, left ventricular ejection fraction. It reduces the degree of left ventricular myocardial hypertrophy. It does not affect myocardial contractility and conduction, does not cause reflex increase in HR, inhibits platelet aggregation, increases glomerular filtration rate, has a weak natriuretic effect.

In diabetic nephropathy it does not increase the severity of microalbuminuria. It has no adverse effect on metabolism and plasma lipid concentration and may be used for therapy of patients with bronchial asthma, diabetes mellitus and gout. Significant decrease in BP is observed after 6-10 hours, the duration of effect is 24 hours.

. In patients with diseases of the cardiovascular system (including coronary atherosclerosis with lesion of one vessel and up to stenosis of 3 or more arteries, atherosclerosis of the carotid arteries), who had myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA) or in patients with angina pectoris the use of amlodipine prevents the development of carotid intima-media thickening, reduces mortality from myocardial infarction, stroke, PTCA, aortocoronary bypass; leads to fewer hospitalizations for unstable angina and progression of CHF; reduces the frequency of interventions to restore coronary blood flow.

The therapy with digoxin, diuretics and ACE inhibitors does not increase risk of death or complications and lethal outcomes in patients with CHF (functional class III-IV according to NYHA classification) during therapy. In patients with CHF (functional class III-IV according to NYHA classification) of non-ischemic etiology during amlodipine use there is a possibility of pulmonary edema development.

Pharmacokinetics

After oral administration amlodipine is well absorbed from the gastrointestinal tract. Mean absolute bioavailability is 64-80%, Tmax in serum is 6-12 h. Css are reached after 7-8 days of therapy.

Eating does not affect absorption of amlodipine. The average Vd is 21 l/kg, indicating that most of the drug is in the tissues and less in the blood. Most of the drug in blood (97.5%) is bound to plasma proteins. Amlodipine undergoes slow but active metabolism in the liver with no significant first-pass effect. Metabolites have no significant pharmacological activity.

After a single dose, the T1/2 ranges from 35 to 50 h; when repeatedly administered, the T1/2 is approximately 45 h. About 60% of oral intake is excreted by kidneys mainly as metabolites, 10% – unchanged, and 20-25% – via intestine with bile. Total clearance of amlodipine is 0.116 ml/s/kg (7 ml/min/kg; 0.42 l/h/kg).

The use in elderly patients. In elderly patients (over 65 years) the excretion of amlodipine is slower (T1/2 – 65 h) compared to younger patients, but this difference has no clinical significance.

The use in patients with hepatic impairment. The prolongation of T1/2 in patients with hepatic impairment suggests that the drug cumulation in the body will be higher with long-term use (T1/2 – up to 60 h).

The use in patients with renal failure. Renal insufficiency has no significant effect on the kinetics of amlodipine.

Amlodipine penetrates through the HEB. It is not eliminated by hemodialysis.

Indications

– Arterial hypertension in adults (both in monotherapy and in combination with other antihypertensive drugs).
– Arterial hypertension in children aged 6-17 years.
– Stable angina and vasospastic angina (Prinzmetal’s angina or variant angina), both in monotherapy and in combination with other antianginal drugs.

Pharmacological effect

A dihydropyridine derivative is a blocker of “slow” calcium channels (SCMC), has a hypotensive and antianginal effect. Blocks “slow” 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 coronary and peripheral arteries and arterioles:

– in case of angina pectoris, it reduces the severity of myocardial ischemia; dilating peripheral arterioles, reduces total peripheral vascular resistance, reduces afterload on the heart, reduces myocardial oxygen demand;
– expanding the 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 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 attacks 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 (BP) over 24 hours (in the patient’s “lying” and “standing” positions).
Orthostatic hypotension with amlodipine is quite rare. Amlodipine 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 (HR), 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. A significant decrease in blood pressure is observed after 6-10 hours, the duration of the effect is 24 hours.

In patients with diseases of the cardiovascular system (including coronary atherosclerosis with damage to one vessel and up to stenosis of 3 or more arteries, atherosclerosis of the carotid arteries), who have had myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA) or in patients with angina pectoris, the use of amlodipine prevents the development of intima-media thickening of the carotid arteries, reduces mortality from myocardial infarction, stroke, PTCA, coronary artery bypass grafting; leads to a decrease in the number of hospitalizations for unstable angina and progression of chronic heart failure (CHF); reduces the frequency of interventions aimed at restoring coronary blood flow.
It does not increase the mortality rate or the development of complications and deaths in patients with CHF (III-IV functional class according to the NYHA classification) during therapy with digoxin, diuretics and angiotensin-converting enzyme (ACE) inhibitors. In patients with CHF (III-IV functional class according to the NYHA classification) of non-ischemic etiology, when using amlodipine, there is a risk of pulmonary edema.
Use in pediatric patients (over 6 years of age)
In a study of 268 children aged 6 to 17 years with predominantly secondary hypertension, a comparison of amlodipine 2.5 mg and 5.0 mg doses with placebo showed that both doses reduced systolic blood pressure to a significantly greater extent than 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 effectiveness of amlodipine in reducing cardiovascular morbidity in childhood and mortality in adulthood has also not been established.

After oral administration, amlodipine is well absorbed from the gastrointestinal tract. The average absolute bioavailability is 64-80%, the maximum concentration in the blood serum is determined after 6-12 hours. Equilibrium concentrations are achieved after 7-8 days of therapy.
Concomitant food intake does not affect the absorption of amlodipine. The mean volume of distribution is 21 L/kg body weight, indicating that most of the drug is in the tissues and a smaller part is in the blood. Most of the drug in the blood (97.5%) binds to blood plasma proteins. Amlodipine undergoes slow but active metabolism in the liver with no significant first pass effect through the liver. Metabolites do not have significant pharmacological activity.
After a single dose, the half-life (T1/2) varies from 35 to 50 hours; with repeated administration, T1/2 is approximately 45 hours. About 60% of the dose taken orally is excreted by the kidneys mainly in the form of metabolites, 10% unchanged, and 20-25% through the intestines with bile. The total clearance of amlodipine is 0.116 ml/s/kg (7 ml/min./kg, 0.42 l/h/kg).
Use in elderly patients
In elderly patients (over 65 years of age), the elimination of amlodipine is slower (T1/2 – 65 hours) compared to young patients, but this difference is not clinically significant.
Use in patients with liver failure
Prolongation of T1/2 in patients with liver failure suggests that with long-term use the accumulation of the drug in the body will be higher (T1/2 – up to 60 hours).
Use in patients with renal failure
Renal failure does not significantly affect the kinetics of amlodipine. Amlodipine penetrates the blood-brain barrier. It is not removed during hemodialysis.
Use in pediatric patients
A population pharmacokinetic study was conducted in 74 hypertensive pediatric patients aged 1 to 17 years (34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) who received amlodipine at a dose of 1.25 to 20 mg once or twice daily. The mean oral clearance (CL/F) in children aged 6 to 12 years and in adolescents aged 13 to 17 years was 22.5 and 27.4 L/h, respectively, in boys and 16.4 and 21.3 L/h, respectively, in girls. Large differences in exposure were observed among patients. Data for children under 6 years of age is limited.

Special instructions

It is necessary to maintain dental hygiene and follow-up with a dentist (to prevent pain, bleeding and gum hyperplasia).
In elderly patients, T1/2 may increase and drug clearance may decrease. No dose changes are required, but more careful monitoring of patients in this category is necessary.
The effectiveness and safety of using Norvasc® in hypertensive crisis has not been established.
Despite the absence of withdrawal syndrome in BMCC, it is advisable to discontinue treatment with Norvasc® by gradually reducing the dose of the drug.
During the use of Norvasc® in patients with chronic heart failure class III and IV functional class according to the NYHA classification of non-ischemic origin, an increase in the incidence of pulmonary edema was noted, despite the absence of signs of worsening heart failure.

Active ingredient

Amlodipine

Composition

1 tablet with a dosage of 5 mg contains:

Active ingredient: amlodipine – 5 mg (in the form of amlodipine besylate – 6.944 mg).

Excipients: microcrystalline cellulose – 124.056 mg, anhydrous calcium hydrogen phosphate – 63 mg, sodium carboxymethyl starch – 4 mg, magnesium stearate – 2 mg.

Pregnancy

The safety of using Norvasc® during pregnancy and breastfeeding has not been established, therefore use during pregnancy and breastfeeding is possible only when the benefit to the mother outweighs the risk to the fetus and newborn.
Experience with the drug shows that amlodipine is excreted into women’s breast milk. The mean milk/plasma ratio for amlodipine concentration was 0.85 among 31 lactating women who had pregnancy-related hypertension and received amlodipine at an initial dosage of 5 mg per day. The dosage of the drug was adjusted if necessary (depending on the average daily dose and weight: 6 mg and 98.7 mcg/kg, respectively). The estimated daily dose of amlodipine received by an infant through breast milk is 4.17 mcg/kg.
There was no effect of amlodipine on fertility in a study in rats.

Contraindications

– Hypersensitivity to amlodipine and other dihydropyridine derivatives, as well as excipients included in the drug.
– Severe arterial hypotension (systolic blood pressure less than 90 mmHg).
– Obstruction of the left ventricular outflow tract (including severe aortic stenosis).
– Shock (including cardiogenic)
– Hemodynamically unstable heart failure after myocardial infarction.
– Children under 6 years of age (efficacy and safety have not been established for arterial hypertension), for other indications the drug is contraindicated in patients under 18 years of age.

Side Effects

The frequency of the adverse reactions listed below was determined according to the following (World Health Organization classification):
very often – more than 1/10
often – from more than 1/100 to less than 1/10
infrequently – from more than 1/1000 to less than 1/100,
rarely – from more than 1/10000 to less than 1/1000,
very rarely – from less than 1/10000, including individual messages,
unknown – frequency cannot be estimated from available data.
From the cardiovascular system: often – a feeling of palpitations, peripheral edema (ankles and feet), “flushes” of blood to the skin of the face; infrequently – excessive decrease in blood pressure; very rarely – fainting, shortness of breath, vasculitis, orthostatic hypotension, development or worsening of CHF, cardiac arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), myocardial infarction, chest pain.
From the musculoskeletal system: infrequently – arthralgia, muscle cramps, myalgia, back pain, arthrosis, rarely – myasthenia gravis.
From the nervous system: often – headaches, dizziness, increased fatigue, drowsiness; uncommon – asthenia, general malaise, hypoesthesia, paresthesia, peripheral neuropathy, tremor, insomnia, mood lability, unusual dreams, increased excitability, depression, anxiety, ringing in the ears, perversion of taste; very rarely – migraine, increased sweating, apathy, agitation, ataxia, amnesia; unknown – extrapyramidal disorders.
From the digestive system: often – nausea, abdominal pain; uncommon – vomiting, constipation or diarrhea, flatulence, dyspepsia, anorexia, dry oral mucosa, thirst; rarely – gum hyperplasia, increased appetite; very rarely – pancreatitis, gastritis, jaundice (caused by cholestasis), hyperbilirubinemia, increased activity of “liver” transaminases, hepatitis.
From the hematopoietic organs: very rarely – thrombocytopenic purpura, leukopenia, thrombocytopenia.
From the respiratory system: infrequently – shortness of breath, rhinitis, nosebleeds; very rarely – cough.
From the senses: infrequently – diplopia, impaired accommodation, xerophthalmia, conjunctivitis, eye pain, visual impairment;
From the genitourinary system: infrequently – frequent urination, painful urination, nocturia, erectile dysfunction; very rarely – dysuria, polyuria.

From the skin: rarely – dermatitis; very rarely – alopecia, xeroderma, cold sweat, skin pigmentation disorder.
Metabolic disorders: very rarely – hyperglycemia; infrequently – increase/decrease in body weight
Allergic reactions: infrequently – skin itching, rash (including erythematous, maculopapular rash, urticaria), very rarely – angioedema, erythema multiforme.
Laboratory indicators: very rarely – hyperglycemia
Other: infrequently – chills, gynecomastia, pain of unspecified localization; very rarely – parosmia.

Interaction

Amlodipine can be safely used for the treatment of arterial hypertension together with thiazide diuretics, alpha-blockers, beta-blockers or ACE inhibitors. In patients with stable angina, amlodipine can be combined with other antianginal agents, for example, long- or short-acting nitrates, beta-blockers.
Unlike other BMCCs, no clinically significant interaction of amlodipine (III generation BMCCs) was found when used together with non-steroidal anti-inflammatory drugs (NSAIDs), including indomethacin.
It is possible to enhance the antianginal and hypotensive effect of BMCC when used together with thiazide and loop diuretics, 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 generally not been observed in amlodipine studies, some CBMCs may enhance the negative inotropic effects of antiarrhythmic drugs that cause QT prolongation (eg, amiodarone and quinidine).
Amlodipine can also be safely used concomitantly with antibiotics and oral hypoglycemic agents.
A single dose of 100 mg of sildenafil 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.
Simvastatin: simultaneous repeated use of amlodipine at a dose of 10 mg and simvastatin at a dose of 80 mg leads to an increase in simvastatin exposure by 77%. In such cases, the dose of simvastatin should be limited to 20 mg.
Ethanol (drinks containing alcohol): amlodipine with single and repeated use in a dose of 10 mg does not affect the pharmacokinetics of ethanol.
Antiviral agents (ritonavir): increases plasma concentrations of BMCC, including amlodipine.
Neuroleptics and isoflurane: enhancing the hypotensive effect of dihydropyridine derivatives.
Calcium supplements can reduce the effect of BMCC.
When BMCC is used together with lithium preparations (no data are available for amlodipine), it is possible that their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus) may increase.
Studies of the simultaneous use of amlodipine and cyclosporine in healthy volunteers and all groups of patients, with the exception of patients after kidney transplantation, have not been conducted. Various studies of the interaction of amlodipine with cyclosporine in patients after kidney transplantation show that the use of this combination may not lead to any effect, or increase the minimum concentration of cyclosporine to varying degrees, up to 40%. These data should be taken into account and cyclosporine concentrations should be monitored in this group of patients when cyclosporine and amlodipine are used concomitantly. Does not affect the serum concentration of digoxin and its renal clearance.
Does not significantly affect the effect of warfarin (prothrombin time).
Cimetidine does not affect the pharmacokinetics of amlodipine.
In in vitro studies, amlodipine does not affect the plasma protein binding of digoxin, phenytoin, warfarin and indomethacin.
Grapefruit juice: simultaneous single administration of 240 mg of grapefruit juice and 10 mg of amlodipine orally is not accompanied by a significant change in the pharmacokinetics of amlodipine. However, it is not recommended to use grapefruit juice and amlodipine at the same time, since genetic polymorphism of the CYP3A4 isoenzyme may increase the bioavailability of amlodipine and, as a result, enhance the hypotensive effect.
Aluminum- or magnesium-containing antacids: their single dose does not have a significant effect on the pharmacokinetics of amlodipine.
Inhibitors of the CYP3A4 isoenzyme: with simultaneous use of diltiazem at a dose of 180 mg and amlodipine at a dose of 5 mg in patients from 69 to 87 years of age with arterial hypertension, there is an increase in systemic exposure of amlodipine by 57%. Concomitant use of amlodipine and erythromycin in healthy volunteers (18 to 43 years of age) does not lead to significant changes in amlodipine exposure (increase in area under the concentration-time curve (AUC) by 22%). Although the clinical significance of these effects is unclear, they may be more pronounced in older patients.
Potent inhibitors of the CYP3A4 isoenzyme (for example, ketoconazole, itraconazole) may increase the plasma concentration of amlodipine to a greater extent than diltiazem. Amlodipine and inhibitors of the CYP3A4 isoenzyme should be used with caution.
Clarithromycin: CYP3A4 inhibitor. Patients taking clarithromycin and amlodipine at the same time have an increased risk of low blood pressure. Patients taking this combination are advised to remain under close medical supervision.
Inducers of the CYP3A4 isoenzyme: there is no data on the effect of inducers of the CYP3A4 isoenzyme on the pharmacokinetics of amlodipine. Blood pressure should be carefully monitored during concomitant use of amlodipine and inducers of the CYP3A4 isoenzyme.
Tacrolimus: When used concomitantly 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.
Mammalian target of rapamycin (mTOR) inhibitors
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.

Overdose

Symptoms: marked decrease in blood pressure with the possible development of reflex tachycardia and excessive peripheral vasodilation (risk of severe and persistent arterial hypotension, including the development of shock and death).
Treatment: gastric lavage, administration of activated charcoal (especially in the first 2 hours after an overdose), maintaining the function of the cardiovascular system, elevated position of the lower extremities, monitoring heart and lung performance, monitoring circulating blood volume (CBV) and diuresis. To restore vascular tone – use vasoconstrictors (in the absence of contraindications to their use); to eliminate the consequences of blockade of calcium channels – intravenous administration of calcium gluconate. Hemodialysis is ineffective.

Storage conditions

At a temperature not higher than 25 C.

Keep out of the reach of children!

Shelf life

4 years.
Do not use after expiration date.

Manufacturer

USA