Amlotop^® (Tablets) Instructions for Use

ATC Code

C08CA01 (Amlodipine)

Active Substance

Amlodipine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Calcium channel blocker

Pharmacotherapeutic Group

BMCC (Bone Mineral Crystal Complex)

Pharmacological Action

A second-generation slow calcium channel blocker, a dihydropyridine derivative. It has antihypertensive and antianginal effects. By binding to dihydropyridine receptors, it blocks calcium channels, reduces the transmembrane transition of calcium ions into the cell (to a greater extent in vascular smooth muscle cells than in cardiomyocytes).

It exerts a long-term dose-dependent antihypertensive effect. The antihypertensive action is due to a direct vasodilating effect on vascular smooth muscles. In arterial hypertension, a single dose provides a clinically significant reduction in blood pressure for 24 hours (in both supine and standing positions). It does not cause a sharp decrease in blood pressure or left ventricular ejection fraction. It does not affect myocardial contractility and conductivity. Reduces the degree of myocardial hypertrophy.

The antianginal effect is due to the expansion of coronary and peripheral arteries and arterioles: in angina pectoris, it reduces the severity of myocardial ischemia; by dilating peripheral arterioles, it reduces total peripheral vascular resistance, reduces cardiac preload, and reduces myocardial oxygen demand. By dilating the main coronary arteries and arterioles in unchanged and ischemic areas of the myocardium, it increases oxygen supply to the myocardium (especially in vasospastic angina); prevents the development of coronary artery constriction (including that caused by smoking).

In patients with angina pectoris, a single daily dose of amlodipine increases the time to the first ischemic episode during physical exertion, prevents the development of angina attacks and ischemic depression of the ST segment (by 1 mm) during physical exertion, and reduces the frequency of angina attacks and nitroglycerin consumption.

In patients with coronary artery disease (including coronary atherosclerosis with single-vessel disease and up to stenosis of 3 or more arteries and carotid artery atherosclerosis), who have had myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA), or suffer from angina, 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, and leads to a reduction in the number of hospitalizations for unstable angina and interventions aimed at restoring coronary blood flow.

Amlodipine does not increase the risk of death or the development of complications leading to death in patients with chronic heart failure (NYHA functional class III-IV) while on therapy with digoxin, diuretics, and ACE inhibitors.

In patients with chronic heart failure (NYHA functional class III-IV) of non-ischemic etiology, there is a possibility of pulmonary edema when using amlodipine.

Amlodipine does not have any adverse effect on metabolism and plasma lipid concentrations. It 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.

Time to onset of effect – 2-4 hours, duration of effect – 24 hours.

Pharmacokinetics

Absorption

After oral administration, Amlodipine is slowly absorbed from the gastrointestinal tract. Bioavailability is 60-65%, C_max in plasma is observed after 6-12 hours. C_ss is achieved after 7-8 days of therapy. Food intake does not affect the absorption of amlodipine.

Distribution

Plasma protein binding is 90-97%. The average V_d is 21 L/kg.

It penetrates the blood-brain barrier. It is excreted in breast milk.

Metabolism

Amlodipine undergoes slow but extensive metabolism (90%) in the liver with the formation of inactive metabolites, has low hepatic clearance (undergoes the “first-pass” effect through the liver).

Excretion

When taking the drug once a day, T_1/2 averages 35 hours (from 35 hours to 50 hours). Total clearance is 500 ml/min. It is excreted by the kidneys (10% unchanged, 60% as metabolites), with bile and through the intestine (20-25% with feces).

Pharmacokinetics in special clinical cases

In elderly patients, patients with hepatic insufficiency, and severe chronic heart failure, T_1/2 increases to 60-65 hours.

In renal failure, T_1/2 does not change.

It is not removed by hemodialysis.

Indications

• Arterial hypertension (as monotherapy or in combination with other antihypertensive agents);
• Stable exertional angina (as monotherapy or in combination with other antianginal agents);
• Vasospastic angina (Prinzmetal’s angina) (as monotherapy or in combination with other antianginal agents).

ICD codes

Dosage Regimen

Tablets

It is prescribed orally, once a day. It is taken regardless of meals, with a sufficient amount of water (100 ml).

For the treatment of arterial hypertension and angina, the initial dose of the drug is 5 mg. Depending on the individual patient response, the dose can be increased to a maximum of 10 mg/day. It is recommended to increase the dose after 7-14 days from the start of therapy. A more rapid dose increase requires careful monitoring of the patient.

For patients with low body weight, patients of short stature, elderly patients, patients with impaired liver function as an antihypertensive agent, Amlodipine is prescribed at an initial dose of 2.5 mg (1/2 tab. 5 mg), as an antianginal agent – 5 mg.

The drug at an initial dose of 2.5 mg can also be used when adding amlodipine to therapy with other antihypertensive drugs.

In patients with renal impairment, no dose adjustment of the drug is required.

Adverse Reactions

Definition of the frequency of adverse reactions: common (>1%), uncommon (>0.1% and <1%), rare (>0.01% and <0.1%), very rare (<0.01%).

From the cardiovascular system: common – peripheral edema (ankles and feet), palpitations, sensation of heat and flushing; uncommon – excessive decrease in blood pressure, orthostatic hypotension, vasculitis; rare – development or worsening of heart failure; very rare – cardiac arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation), myocardial infarction, chest pain.

From the central and peripheral nervous system: common – increased fatigue, dizziness, headache, drowsiness; uncommon – malaise, fainting, increased sweating, asthenia, hypoesthesia, paresthesia, peripheral neuropathy, tremor, insomnia, emotional lability, unusual dreams, nervousness, depression, anxiety; rare – convulsions, apathy, agitation; very rare – ataxia, amnesia, migraine.

From the digestive system: common – abdominal pain, nausea; uncommon – vomiting, constipation, flatulence, dyspepsia, diarrhea, anorexia, dry mouth, thirst; rare – gingival hyperplasia, increased appetite; very rare – gastritis, pancreatitis, hyperbilirubinemia, jaundice (usually cholestatic), increased activity of liver transaminases, hepatitis.

From the hematopoietic system: very rare – thrombocytopenic purpura, leukopenia, thrombocytopenia.

From the musculoskeletal system: uncommon – arthralgia, muscle cramps, myalgia, back pain, arthrosis; rare – myasthenia.

From metabolism uncommon – increase/decrease in body weight; very rare – hyperglycemia.

From the respiratory system: uncommon – dyspnea, rhinitis, epistaxis; very rare – cough.

From the urinary system: uncommon – frequent urination (pollakiuria), painful urge to urinate, nocturia; very rare – dysuria, polyuria.

From the senses uncommon – tinnitus, visual disturbances, diplopia, accommodation disturbance, xerophthalmia, conjunctivitis, eye pain, taste perversion; very rare – parosmia.

Dermatological reactions uncommon – alopecia; rare – dermatitis; very rare – xeroderma, skin pigmentation disorder.

Allergic reactions: uncommon – skin itching, rash; very rare – angioedema, erythema multiforme, urticaria.

Other: uncommon – gynecomastia, chills, impotence; very rare – cold sweat.

Contraindications

• Severe arterial hypotension (systolic blood pressure less than 90 mm Hg);
• Collapse;
• Cardiogenic shock;
• Clinically significant aortic stenosis;
• Pregnancy;
• Lactation period;
• Age under 18 years (efficacy and safety not established);
• Lactose intolerance, lactase deficiency or glucose-galactose malabsorption;
• Hypersensitivity to the components of the drug;
• Hypersensitivity to other dihydropyridine derivatives.

With caution, the drug should be used in cases of impaired liver function, sick sinus syndrome (severe bradycardia, tachycardia), chronic heart failure of non-ischemic etiology NYHA functional class III-IV, arterial hypotension (systolic blood pressure greater than 90 and less than 100 mm Hg), aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, in acute myocardial infarction (and within 1 month after), in elderly patients.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and lactation (breastfeeding).

Women of childbearing potential should use reliable methods of contraception during treatment with amlodipine.

Use in Hepatic Impairment

The drug should be used with caution in cases of impaired liver function.

In patients with hepatic insufficiency, an increase in T_1/2 is expected, and with long-term administration, the accumulation of the drug in the body will be higher (T_1/2 – up to 60 hours).

Use in Renal Impairment

Renal failure does not significantly affect the kinetics of amlodipine.

Pediatric Use

Contraindicated for use in patients under 18 years of age (efficacy and safety not established).

Geriatric Use

The drug should be used with caution in elderly patients.

The dosage regimen for the elderly is the same as for patients of other age groups. When increasing the dose, careful monitoring of elderly patients is necessary.

Special Precautions

In the treatment of arterial hypertension, Amlodipine can be used in combination with thiazide diuretics, alpha- and beta-blockers, ACE inhibitors, short- and long-acting nitrates, NSAIDs, antibiotics, and oral hypoglycemic agents.

In the treatment of angina, Amlodipine can be prescribed as monotherapy or in combination with other antianginal drugs, including in patients refractory to treatment with nitrates and/or beta-blockers in adequate doses.

During treatment, it is necessary to monitor body weight and sodium intake. Oral hygiene and regular dental visits must be observed (to prevent soreness, bleeding, and gingival hyperplasia).

Amlodipine does not affect plasma concentrations of potassium, glucose, triglycerides, total cholesterol, LDL, uric acid, creatinine, and blood urea nitrogen and can be used in patients with bronchial asthma, diabetes mellitus, and gout.

Amlodipine can be used in patients prone to vasospasm/vasoconstriction.

Patients with low body weight or short stature, elderly patients, and patients with severe hepatic insufficiency may require lower doses. When increasing the dose, careful monitoring of elderly patients is necessary.

Although calcium channel blockers do not have a withdrawal syndrome, it is recommended to gradually reduce the dose before discontinuing treatment.

Amlodipine tablets are not recommended for hypertensive crisis.

Effect on ability to drive vehicles and operate machinery

In some patients, mainly at the beginning of treatment or when changing the dosage regimen, drowsiness, dizziness, and other side effects may occur due to a possible pronounced decrease in blood pressure. If they occur, driving vehicles and operating machinery is not recommended.

Overdose

Symptoms pronounced decrease in blood pressure with possible development of reflex tachycardia and excessive peripheral vasodilation (risk of developing pronounced and persistent decrease in blood pressure, including with the development of shock and fatal outcome).

Treatment intake of activated charcoal (especially within the first 2 hours after overdose), gastric lavage (in some cases), maintenance of cardiovascular function, monitoring of heart and lung function indicators, monitoring of circulating blood volume and diuresis. The patient should be placed in a horizontal position with elevated lower limbs.

If there are no contraindications – symptomatic therapy: vasoconstrictor drugs, intravenous administration of calcium gluconate. Hemodialysis is ineffective.

Drug Interactions

Inhibitors of microsomal oxidation increase the plasma concentration of amlodipine (increasing the risk of side effects), and inducers of hepatic microsomal enzymes decrease the concentration of amlodipine.

Unlike other slow calcium channel blockers, no clinically significant interaction of amlodipine with NSAIDs, especially indomethacin, has been noted.

Enhancement of the antianginal and antihypertensive effects of slow calcium channel blockers is possible when used concomitantly with thiazide and “loop” diuretics, beta-blockers, alpha₁-blockers, verapamil, ACE inhibitors, and nitrates.

With simultaneous use of slow calcium channel blockers with antipsychotics and isoflurane, an increase in the hypotensive effect is possible.

Some slow calcium channel blockers may enhance the pronounced negative inotropic effect of antiarrhythmic drugs that cause QT interval prolongation (amiodarone, quinidine), however, when using Amlodipine, a negative inotropic effect is usually not observed.

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

With the combined use of slow calcium channel blockers with lithium preparations, an increase in the manifestations of their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus) is possible, but data on the drug Amlodipine are lacking.

Cimetidine does not affect the pharmacokinetics of amlodipine.

Amlodipine does not cause significant changes in the pharmacokinetics of cyclosporine. A single dose of antacids containing aluminum/magnesium does not significantly affect the pharmacokinetics of amlodipine.

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

Repeated simultaneous administration of amlodipine at a dose of 10 mg and atorvastatin at a dose of 80 mg does not significantly affect the pharmacokinetics of atorvastatin.

With simultaneous use of digoxin and amlodipine, the serum concentration of digoxin and its clearance do not change.

Amlodipine does not affect the change in prothrombin time caused by warfarin.

Single and repeated use of amlodipine at a dose of 10 mg does not significantly affect the pharmacokinetics of ethanol.

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

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

Storage Conditions

List B. The drug should be stored out of the reach of children, in a dry, light-protected place, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.