The Order of Ministry of
Health of Ukraine
24.01.2019 № 192
for medical use
active substance: S(-) amlodipine besylate;
1 tablet contains S(-) amlodipine besylate equivalent to S(-) amlodipine 2.5 mg or 5 mg;
excipients: microcrystalline cellulose, calcium hydrogen phosphate dehydrate, yellow ferric oxide (E 172), anhydrous colloidal silicon dioxide, sodium starch glycolate (type A), magnesium stearate.
Pharmaceutical form. Tablets.
Main physico-chemical properties: round flat faced, light yellow beveled tablets with «K» logo on one side.
Pharmacotherapeutic group. Selective calcium antagonists with predominant vascular influence on vessels.
ATC code С08С А01.
Amlodipine is a racemic mixture of S (-) and R (+) isomers. S (-) amlodipine is active chiral form of amlodipine, calcium antagonist (dihydropyridine derivative), which blocks the flow of calcium ions to the myocardium and to smooth muscle cells.
The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism of antianginal effect of amlodipine is not fully determined, but its following effects have a certain role.
1. Amlodipine dilates peripheral arterioles and thus, reduces the peripheral resistance (afterload). Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
2. The expansion of major coronary arteries and coronary arterioles (normal and ischemic) may also play a role in the mechanism of action of amlodipine. Such an expansion enhances myocardial saturation with oxygen in patients with coronary artery spasm (Prinzmetal’s angina or variant angina).
In patients with arterial hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of amlodipine action, acute arterial hypotension is not observed.
In patients with cardiac angina when using one daily dose of the drug, the total physical activity time, time to the beginning of angina and time to 1 mm depression of the segment of ST increases. The drug reduces the frequency of angina attacks and reduces the necessity of nitroglycerin administration.
Amlodipine has not been associated with any adverse metabolic effects or changes in blood plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.
After oral administration of therapeutic doses, amlodipine is gradually absorbed in blood plasma. The absorption of amlodipine is not influenced by concomitant intake of food. The absolute bioavailability of unmodified molecule is about 64-80%. Maximum blood plasma concentration is between 6-12 hours after administration. The volume of distribution is approximately 21 l/kg; acid dissociation constant (рКа) of amlodipine is 8.6. In vitro studies have shown that approximately 97.5% of amlodipine is bound to blood plasma proteins.
The blood plasma elimination half-life is about 35-50 hours. The steady state concentration in blood plasma is reached after 7-8 days of continuous drug administration.Amlodipine is mainly metabolized to the formation of active metabolites. About 60% of the administered dose is excreted in the urine, approximately 10% of which is unchanged amlodipine.
The time to achieve steady state concentrations of amlodipine in blood plasma is similar in elderly patients and in younger patients. The clearance of amlodipine is usually lower, which leads to an increase in the area under the "concentration / time" (AUC) and half-life of the drug 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 amlodipine blood plasma concentration are not correlated with the degree of renal impairment. In patients with renal impairment amlodipine may be administered at the normal dosage. Amlodipine is not removed by dialysis.
Patients with hepatic impairment.
Information about amlodipine administration in patients with hepatic impairment is very limited. In patients with hepatic impairment, clearance of amlodipine is reduced, which leads to an increase in the half-life and an increase in AUC by about 40-60%.
– Arterial hypertension.
– Chronic stable angina.
– Vasospastic angina pectoris (Prinzmetal's angina).
– Knownhypersensitivity to dihydropyridine, amlodipine and any other excipient of the drug.
– Severe arterial hypotension.
– Shock (including cardiogenic shock).
– Obstruction of the left ventricular drainage tract (e.g. severe aortic stenosis).
– Hemodynamically unstable heart failure after acute myocardial infarction.
Interaction with other medicinal products and other forms of interaction.
Effects of other medicinal products on amlodipine.
Available data on the safe use of amlodipine with thiazide diuretics, alpha blockers, beta-blockers, ACE inhibitors, prolonged-release nitrates, sublingual form of nitroglycerin, non-steroidal anti-inflammatory drugs, antibiotics, oral hypoglycemic drugs.
Data from in vitro human plasma studies indicate that amlodipine has no effect on binding to the blood proteins of the investigational medicinal products (digoxin, phenytoin, warfarin or indomethacin).
The concomitant use of amlodipine and potent or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may lead to significant increase in amlodipine exposure, which may also lead to the increased risk of hypotension. The clinical relevance of these variations may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may thus be required.
It is not recommended to use amlodipine and grapefruit or grapefruit juice at the same time, since in some patients the bioavailability of amlodipine may increase, which leads to hypotensive effects increasing.
The concentration of amlodipine in the plasma may change after the simultaneous use of known CYP3A4 inducers. Therefore, monitoring of blood pressure and adjusting the dose should be considered taking into account the simultaneous administration of these drugs, both during and after concomitant treatment, especially with strong inducers of CYP3A4 (e.g. rifampicin, St. John's wort).
In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalemia, after administration of verapamil and dantrolene intravenous. Due to risk of hyperkalemia, it is recommended to avoid co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the treatment of malignant hyperthermia.
Effect of amlodipine on other medicinal products.
Hypotensive effect of amlodipine potentiates the antihypertensive effect of other antihypertensive drugs. Amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, warfarin.
There is a risk of increase in the blood levels of tacrolimus when concomitant use with amlodipine, however, pharmacokinetic mechanism of such interaction is not completely determined. Regular monitoring of tacrolimus blood levels is necessary and dosage adjustment if required to avoid the toxicity of tacrolimus, when concomitantly using amlodipine.
Inhibitors of mTOR.
mTOR inhibitors, such as syrrolimus, temsirolimus and everolimus, are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When administered concurrently, amlodipine may increase the exposure of mTOR inhibitors.
There have been no studies of interaction between cyclosporine and amlodipine in healthy volunteers or other groups, except for the use in patients with a transplanted kidney, which had a transient increase of residual concentration of cyclosporine (on average by 0–40%). For patients with a transplanted kidney using amlodipine, the possibility of monitoring of cyclosporine concentrations should be considered, and if required, the dose of cyclosporine should be decreased.
Concomitant use of multiple doses of amlodipine 10 mg and simvastatin 80 mg increased exposure to simvastatin by 77% compared to using simvastatin only. For patients using amlodipine, simvastatin dose should be limited to 20 mg per day.
Clinical studies of drug interaction have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.
A single and multiple dose of amlodipine 10 mg did not have a significant effect on the pharmacokinetics of ethanol.
The co-administration of amlodipine with cimetidine had no effect on the pharmacokinetics of amlodipine.
The co-administration of aluminum / magnesium (antacids) with a single dose of amlodipine did not have a significant effect on the pharmacokinetics of amlodipine.
Impact on laboratory test values is unknown.
Safety and efficacy of amlodipine administration in hypertensive crisis have not been estimated.
Patients with heart failure.
Amlodipine should be used with caution in this category of patients. It has been shown patients with severe heart failure (class III and IV according to NYHA classification)when using amlodipine, the incidence of pulmonary edema is increasing. Patients with congestive heart failure, calcium channel blockers, including amlodipine, should be used with caution as they can increase the risk of cardiovascular events and fatal events in the future.
Patients with hepatic impairment.
The half-life of amlodipine and parameters AUC higher in patients with hepatic impairment; there are no recommendations for drug dosage. Therefore, the drug should be started with the lowest dose in this population. Caution should be exercised when starting to administer the drug, and when increasing the dose. Slow dose titration and careful control may be required in patients with severe hepatic impairment.
Caution should be exercised when increasing the drug dose in these patients.
Patients with renal insufficiency.
Usual drug doses should be administered to these patients. Changes in the amlodipine blood plasma concentration do not correlate with the degree of renal dysfunctions.
Amlodipine can not be removed by dialyses.
Amlodipine does not affect the results of laboratory tests.
Consumption of grapefruits or grapefruit juice is not recommended while taking amlodipine, because the bioavailability of amlodipine may be increased in some patients, which leads to increased hypotensive effect.
Use during pregnancy or breast feeding.
Safety of use of amlodipine in pregnant women is not determined.
Amlodipine should not be used during pregnancy only if there is no safer alternative and the risk, associated with the disease overweighs the possible harm of treatment for the mother and fetus.
Animal studies have shown reproductive toxicity at high doses.
Amlodipine is excreted into breast milk. The amount of amlodipine that can enter a baby with breast milk in a mother can range from 3-7 to 15% of the dose used by the mother. The effect of amlodipine on newborns is unknown. When deciding whether to breast-feed or on the use of amlodipine, the benefits of breast-feeding for the baby and the benefits of using the drug for the mother should be considered.
Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility.
Ability to influence on reaction rate while driving a car or operating any other mechanisms.
Amlodipine may have minor or moderate influence on the ability to drive a car or operate other machines.The reaction rate may be reduced if there are symptoms such as dizziness, headache, confusion or nausea.
Caution should be exercised, especially while initiating the treatment.
Dosage and administration.
For the treatment of arterial hypertension and angina pectoris, the starting dose of Samlopin® is S (-) amlodipine 2.5 mg once daily. The dose can be increased to a maximum 5 mg of S (-) amlodipine once daily, depending on the individual response of the patient. In patients suffering from angina pectoris, amlodipine can be used as monotherapy or in combination with anti-anginal medicinal products in a case of resistance to nitrates and/or adequate doses of beta-blockers.
There is experience of using the drug in combination with thiazide diuretics, alpha-blockers, beta-blockers and ACE inhibitors for patients with arterial hypertension.
There is no need to adjust the drug dosage when using concomitantly with thiazide diuretics, beta-blockers and ACE inhibitors.
The dose adjustment is not required in these patients. Caution should be exercised when increasing the dose.
Patients with renal impairment.
The normal dosage is recommended,because changes in blood plasma amlodipine concentration are not associated with the severity of renal failure. Amlodipine do not remove by dialyses.
Use in patients with hepatic impairment.
Doses of the drug for use in patients with mild to moderate hepatic dysfunction have not been established, therefore, the dose should be carefully monitored and administered at the lowest dose (see “Pharmacological Properties”, “Pharmacokinetics”, and “Administration details”).
Pharmacokinetic of amlodipine has not been studied in patients with severe hepatic impairment. In patients with severe hepatic impairment the use of amlodipine should be started with the lowest dose and gradually increased.
Samlopin® tablets 2.5 mg are not intended to be divided into halves to get a dose of 1.25 mg.
Samlopin® tablets 5 mg are not intended to be divided into halves to get a dose of 2.5 mg.
The safety use of S(-) amlodipine in children is not proved. The drug is contraindicated to be administered in this category of patients.
The experience with intentional overdose of amlodipine is limited.
Symptoms of overdose: available information suggests that a significant overdose of amlodipine will result in excessive peripheral vasodilation and, possibly, reflex tachycardia. Significant and possibly prolonged systemic hypotension, including lethal shock, has been reported.
Treatment:clinically significant hypotension due to overdose of amlodipine requires active support for the cardiovascular system, including frequent monitoring of cardiac and respiratory function, lifting of the lower extremities, monitoring of the volume of circulating fluid and urinary excretion.
Vascular tone and blood pressure can be used to restore vasoconstrictive drugs, making sure there are no contraindications to their use. The use of calcium gluconate intravenously may be useful for leveling the effects of the blockade of calcium channels.
In some cases, gastric lavage may be beneficial. The use of activated carbon for healthy volunteers within 2 hours after the administration of 10 mg of amlodipine significantly reduced its absorption.
Since amlodipine is highly bound to proteins, the effect of dialysis is negligible.
Blood and lymphatic system: leukocytopenia, thrombocytopenia, purpura, anemia, agranulocytosis.
Immune system: allergic reactions.
Metabolism and alimentary disorders: hyperglycemia, thirst.
Psychiatric: insomnia, nervousness, mood changes (including anxiety), depression, confusion, unconsciousness, insomnia, depersonalization.
Nervous system: drowsiness, dizziness, headache (especially at the beginning of treatment), tremor, dysgeusia, syncope, hypesthesia, paresthesia, hypertonia, peripheral neuropathy, extrapyramidal syndrome.
Visual organs: visual disturbances (including diplopia), conjunctivitis, eye pain.
Acoustic organs and labyrinth: tinnitus, sonitus.
Cardiac: palpitation, tachycardia, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), angina attack, orthostatic (postural) hypotension, collapse, chest pain.
Vascular: flushing, arterial hypotension, vasculitis, peripheral ischemia.
Respiratory, thoracic and mediastinal disorders: dyspnea, rhinitis, cough, epistaxis.
Gastro-intestinal tract: anorexia, loss of appetite, epigastric discomfort, abdominal pain, nausea, vomiting, dyspepsia, intestinal dysperistalsis (including constipation and diarrhea), flatulence, bowel dysfunction, dry mouth, dysphagia, pancreatitis, gastritis, gingival hyperplasia, changes in taste.
Hepatobiliary system: hepatitis, including fulminant hepatitis, jaundice, increased liver enzymes (most often associated with cholestasis), hyperbilirubinemia, impaired liver function.
Skin and subcutaneous tissue: alopecia, purpura, skin discoloration, skin depigmentation, increased sweating, itching, rash, eczema, angioedema, multiforme erythema, erythematous rash, maculopapular rash, urticaria, exfoliative dermatitis, Stevens-Johnson Syndrome, toxic epidermal necrolysis, Quincke's edema, photosensitivity.
Musculoskeletal and connective tissue: swollen legs, arthralgia, myalgia, muscle cramps, back pain, muscle stiffness.
Renal and urinary tract: inappropriate urination, nycturia, increased frequency of urination.
Reproductive system and mammary gland: impotence, gynecomastia, sexual dysfunction.
General disorders and administration site: swelling, increased fatigue, chest pain, asthenia, pain, malaise.
Investigations: increase or decrease in body weight.
Shelf-life. 3 years.
Store in the original pack at the temperature NMT 25С.
Keep it out of reach of children.
14 tablets are in blisters; 2 or 4, or 6 blisters are in a carton box.
Conditions of supply. On prescription.
“KUSUM PHARM” LLC
40020, Ukraine, Sumy region, Sumy, Skryabina Str., 54.
Date of last revision.
24.01.2019 № 192
1 tablet contains S(-)amlodipine besylate which is equivalent to S(-)amlodipine 2.5 mg and 5 mg; Selective calcium antagonists with predominant influence on vasculars.
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