Instructions for use Semlopin tablets 2.5 mg No. 28
Composition
active ingredient: S(-) amlodipine besylate;
1 tablet contains S(-) amlodipine besylate equivalent to S(-) amlodipine 2.5 mg;
Excipients: microcrystalline cellulose, calcium hydrogen phosphate dihydrate, yellow iron oxide (E 172), colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: light yellow round, flat-cylindrical tablets with a bevel and the “K” logo on one side.
Pharmacotherapeutic group
Selective calcium antagonists with a predominant effect on blood vessels.
ATX code C08C A01.
Pharmacological properties
Pharmacodynamics
Amlodipine is a racemic mixture of S(-) and R(+) isomers. S(-) amlodipine is the active chiral form of amlodipine, a calcium antagonist (dihydropyridine derivative) that blocks the entry of calcium ions into the myocardium and smooth muscle cells.
The mechanism of the hypotensive action of amlodipine is due to a direct relaxing effect on vascular smooth muscle. The exact mechanism of the antianginal effect of amlodipine is not well defined, but the following effects play a role.
1. Amlodipine dilates peripheral arterioles and thus reduces peripheral resistance (afterload). Since the heart rate remains stable, the reduced workload on the heart leads to a decrease in energy consumption and myocardial oxygen demand.
2. Dilation of the main coronary arteries and coronary arterioles (normal and ischemic) may also play a role in the mechanism of action of amlodipine. Such dilation increases myocardial oxygen saturation in patients with coronary artery spasm (Prinzmetal's angina or variant angina).
In patients with arterial hypertension, the use of the drug 1 time per day provides a clinically significant reduction in blood pressure for 24 hours in both the supine and standing positions. Due to the slow onset of action of amlodipine, acute arterial hypotension is usually not observed.
In patients with angina pectoris, a single daily dose of the drug increases the total time of physical exertion, the time to the onset of angina pectoris, and the time to 1 mm of ST-segment depression. The drug reduces the frequency of angina attacks and reduces the need for nitroglycerin.
Amlodipine is not associated with any adverse metabolic effects or changes in plasma lipid levels and can be used in patients with asthma, diabetes mellitus, and gout.
Pharmacokinetics
Suction/distribution
After oral administration of therapeutic doses, amlodipine is gradually absorbed into the blood plasma. Simultaneous food intake does not affect the absorption of amlodipine. The absolute bioavailability of the unchanged molecule is approximately 64-80%. Maximum plasma concentration is achieved within 6-12 hours after administration. The volume of distribution is approximately 21 l/kg; the acid dissociation constant (pKa) of amlodipine is 8.6. In vitro studies have shown that the binding of amlodipine to plasma proteins is approximately 97.5%.
Metabolism/excretion
The plasma elimination half-life is approximately 35-50 hours. Steady-state plasma concentrations are reached after 7-8 days of continuous dosing. Amlodipine is primarily metabolized to inactive metabolites. Approximately 60% of the administered dose is excreted in the urine, of which approximately 10% is unchanged amlodipine.
Elderly patients
The time to reach steady-state plasma concentrations of amlodipine is similar in elderly and younger adults. The clearance of amlodipine is usually somewhat reduced, resulting in an increase in the area under the concentration-time curve (AUC) and half-life in elderly patients.
Patients with renal impairment
Amlodipine is extensively biotransformed to inactive metabolites. 10% of amlodipine is excreted unchanged in the urine. Changes in plasma concentrations of amlodipine do not correlate with the degree of renal impairment. Patients with renal impairment can use the usual doses of amlodipine. Amlodipine is not removed by dialysis.
Patients with liver dysfunction
Information on the use of amlodipine in patients with hepatic impairment is very limited. In patients with hepatic insufficiency, the clearance of amlodipine is reduced, resulting in a prolonged half-life and an increase in AUC by approximately 40-60%.
Indication
Arterial hypertension. Chronic stable angina. Vasospastic angina (Prinzmetal's angina).
Contraindication
Known hypersensitivity to dihydropyridines, amlodipine or any of the other ingredients of the drug. Severe arterial hypotension. Shock (including cardiogenic shock). Obstruction of the left ventricular outflow tract (e.g. severe aortic stenosis). Hemodynamically unstable heart failure after acute myocardial infarction.
Interaction with other medicinal products and other types of interactions
There is no data on the safe use of amlodipine with thiazide diuretics, alpha-blockers, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
Data obtained in vitro in human plasma indicate that amlodipine has no effect on the protein binding of the drugs tested (digoxin, phenytoin, warfarin, or indomethacin).
CYP3A4 inhibitors
Concomitant use of amlodipine and strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may lead to a significant increase in amlodipine exposure, which may also lead to an increased risk of hypotension. The clinical significance of such changes may be more pronounced in elderly patients. Clinical monitoring of the patient and dose adjustment may be necessary.
It is not recommended to use amlodipine and grapefruit or grapefruit juice simultaneously, since in some patients the bioavailability of amlodipine may increase, which in turn leads to increased hypotensive effect.
CYP3A4 inducers
Plasma concentrations of amlodipine may be altered following concomitant use of known CYP3A4 inducers. Therefore, blood pressure should be monitored and the dose adjusted to take into account the concomitant use of these medicinal products both during and after concomitant treatment, especially with strong CYP3A4 inducers (e.g. rifampicin, St. John's wort).
Dantrolene (infusion)
Fatal ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been observed in animals following intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, it is recommended that calcium channel blockers such as amlodipine be avoided in patients predisposed to malignant hyperthermia and in the treatment of malignant hyperthermia.
Effect of amlodipine on other medicinal products
The hypotensive effect of amlodipine potentiates the hypotensive effect of other antihypertensive agents. Amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Tacrolimus
There is a risk of increased blood levels of tacrolimus when co-administered with amlodipine, but the pharmacokinetic mechanism of this interaction has not been fully established. To avoid tacrolimus toxicity when co-administered with amlodipine, regular monitoring of tacrolimus blood levels and, if necessary, dosage adjustment are required.
mTOR inhibitors
mTOR inhibitors such as sirolimus, temsirolimus and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. Co-administration of amlodipine may result in increased exposure to mTOR inhibitors.
Cyclosporine
No interaction studies have been conducted with ciclosporin and amlodipine in healthy volunteers or other populations, except in renal transplant patients, where a variable increase in ciclosporin trough concentrations (mean 0-40%) was observed. In renal transplant patients receiving amlodipine, monitoring of ciclosporin concentrations should be considered and, if necessary, a reduction in the ciclosporin dose should be considered.
Simvastatin
Co-administration of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. For patients taking amlodipine, the dose of simvastatin should be limited to 20 mg daily.
Other medicines
Clinical drug interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Ethanol (alcohol)
Single and multiple doses of 10 mg amlodipine had no significant effect on the pharmacokinetics of ethanol.
Co-administration of amlodipine with cimetidine had no effect on the pharmacokinetics of amlodipine.
Co-administration of aluminum/magnesium preparations (antacids) with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
Laboratory tests
The effect on laboratory test results is unknown.
Application features
The safety and efficacy of amlodipine in hypertensive crisis have not been evaluated.
Patients with heart failure
Amlodipine should be used with caution in this patient population. An increased incidence of pulmonary edema has been reported in patients with severe heart failure (NYHA class III and IV). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.
The half-life of amlodipine and AUC parameters are longer in patients with impaired liver function; there are no recommendations for the dosage of the drug. Therefore, this category of patients should start using the drug with the lowest dose. Caution should be exercised both at the beginning of the drug and when increasing the dose. Patients with severe hepatic insufficiency may require slow dose selection and careful monitoring of the patient's condition.
Elderly patients
Increasing the dose of the drug in this category of patients should be done with caution.
Patients with renal insufficiency
This category of patients should use the usual doses of the drug. Changes in the concentration of amlodipine in the blood plasma do not correlate with the degree of renal dysfunction.
Amlodipine is not removed by dialysis.
Amlodipine does not affect the results of laboratory tests.
It is not recommended to use amlodipine with grapefruit or grapefruit juice, as bioavailability may be increased in some patients, leading to increased hypotensive effect of the drug.
Ability to influence reaction speed when driving vehicles or other mechanisms
Amlodipine may have minor or moderate influence on the ability to drive and use machines.
Reaction speed may be reduced in the presence of symptoms such as dizziness, headache, confusion or nausea.
Caution should be exercised, especially at the beginning of therapy.
Use during pregnancy or breastfeeding
The safety of amlodipine for use in women during pregnancy has not been established.
The use of amlodipine during pregnancy is recommended only in cases where there is no safer alternative and the risk associated with the disease itself outweighs the possible harm from treatment for the mother and fetus.
In animal studies, reproductive toxicity was observed at high doses.
Breastfeeding period
Amlodipine is excreted in breast milk. The amount of amlodipine that can reach the child with breast milk may be from 3-7 to 15% of the dose taken by the mother. The effect of amlodipine on newborns is unknown. When making a decision on whether to continue breastfeeding or to use amlodipine, the benefit of breastfeeding for the child and the benefit of the drug for the mother should be assessed.
Fertility
Reversible biochemical changes in the sperm head have been reported in some patients receiving calcium channel blockers. There is insufficient clinical information on the potential effect of amlodipine on fertility.
Method of administration and doses
Adults
For the treatment of hypertension and angina pectoris, the usual starting dose of Cemlopin® is 2.5 mg S(-) amlodipine once daily. Depending on the patient's response to therapy, the dose may be increased to a maximum dose of 5 mg S(-) amlodipine once daily.
In patients with angina pectoris, the drug can be used as monotherapy or in combination with other antianginal drugs in case of resistance to nitrates and/or adequate doses of beta-blockers.
There is experience with the use of the drug in combination with thiazide diuretics, alpha-blockers, beta-blockers, or ACE inhibitors in patients with arterial hypertension.
There is no need to adjust the dose of the drug when used simultaneously with thiazide diuretics, beta-blockers and ACE inhibitors.
Elderly patients
No dose adjustment is necessary for this patient group. Dose increases should be made with caution.
Patients with renal impairment
It is recommended to use the usual doses of the drug, since changes in plasma concentrations of amlodipine are not associated with the severity of renal failure. Amlodipine is not excreted by dialysis.
Use in patients with hepatic impairment
The dosage of the drug for use in patients with mild to moderate hepatic impairment has not been established, therefore dose selection should be carried out with caution and use should be started with the lowest dose (see sections "Pharmacodynamics. Pharmacokinetics" and "Special instructions for use").
The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. In patients with severe hepatic impairment, amlodipine should be started at the lowest dose and titrated gradually.
Semlopin® 2.5 mg tablets are not intended to be divided in half to obtain a 1.25 mg dose.
Semlopin® 5 mg tablets are not intended to be divided in half to obtain a 2.5 mg dose.
Children
The safety of S(-) amlodipine in children has not been established. The drug is contraindicated for use in this age group of patients.
Overdose
Experience with intentional overdose of amlodipine is limited.
Treatment: Clinically significant hypotension due to amlodipine overdose requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of the lower extremities, monitoring of circulating fluid volume and urine output.
Vasoconstrictors can be used to restore vascular tone and blood pressure, making sure there are no contraindications to their use. Intravenous calcium gluconate may be useful for reversing the effects of calcium channel blockade.
Gastric lavage may be useful in some cases. Administration of activated charcoal to healthy volunteers within 2 hours of administration of 10 mg of amlodipine significantly reduced its absorption.
Since amlodipine is extensively protein bound, the effect of dialysis is negligible.
Adverse reactions
Blood and lymphatic system disorders: leukocytopenia, thrombocytopenia, purpura, anemia, agranulocytosis.
On the part of the immune system: allergic reactions.
Metabolism and nutritional disorders: hyperglycemia, thirst.
Psychiatric: insomnia, nervousness, mood changes (including anxiety), depression, confusion, loss of consciousness, sleep disturbances, depersonalization.
Nervous system: drowsiness, dizziness, headache (mainly at the beginning of treatment), tremor, dysgeusia, syncope, hypoesthesia, paresthesia, hypertonicity, peripheral neuropathy, extrapyramidal syndrome.
On the part of the organs of vision: visual impairment (including diplopia), conjunctivitis, eye pain.
From the side of the organs of hearing and labyrinth: ringing in the ears, tinnitus.
Cardiac: palpitations, tachycardia, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), angina attacks, orthostatic (postural) hypotension, collapse, chest pain.
Vascular disorders: hot flashes, hypotension, vasculitis, peripheral ischemia.
Respiratory, thoracic and mediastinal disorders: dyspnea, rhinitis, cough, epistaxis.
Gastrointestinal: anorexia, loss of appetite, epigastric discomfort, abdominal pain, nausea, vomiting, dyspepsia, intestinal motility disorders (including constipation and diarrhea), flatulence, intestinal dysfunction, dry mouth, dysphagia, pancreatitis, gastritis, gingival hyperplasia, change in taste.
From the hepatobiliary system: hepatitis, including fulminant hepatitis, jaundice, increased liver enzymes (most often associated with cholestasis), hyperbilirubinemia, impaired liver function.
Skin and subcutaneous tissue disorders: alopecia, purpura, skin discoloration, skin pigmentation disorders, increased sweating, itching, rash, exanthema, angioedema, erythema multiforme, erythematous rash, maculopapular rash, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, Quincke's edema, photosensitivity.
Musculoskeletal and connective tissue disorders: leg swelling, arthralgia, myalgia, muscle cramps, back pain, muscle rigidity.
Renal and urinary disorders: urinary disorders, nocturia, increased urinary frequency.
From the reproductive system and mammary glands: impotence, gynecomastia, sexual dysfunction.
General disorders and administration site conditions: edema, fatigue, chest pain, asthenia, pain, malaise.
Research: increase or decrease in body weight.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
14 tablets in blisters; 2 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
"KUSUM FARM" LLC.
Location of the manufacturer and its business address
40020, Ukraine, Sumy region, Sumy city, Skryabina st., 54.
