Instructions for use Amlodipine-Teva tablets 5 mg blister No. 90
Composition
active ingredient: amlodipine;
1 tablet contains 6.944 mg of amlodipine besylate, equivalent to 5 mg of amlodipine, or 13.888 mg of amlodipine besylate, equivalent to 10 mg of amlodipine;
excipients: microcrystalline cellulose, calcium hydrogen phosphate anhydrous, sodium starch glycolate (type A), magnesium stearate.
Dosage form
Pills.
Main physicochemical properties:
5 mg tablets: round white tablets, 8 mm in diameter, slightly curved, with a break line and embossed "A5" on one side and slightly convex, smooth on the other;
10 mg tablets: round white tablets, 11 mm in diameter, slightly curved, with a break line and embossed "A10" on one side and slightly convex, smooth on the other.
Pharmacotherapeutic group
Selective calcium antagonists with a predominant effect on blood vessels. ATC code C08C A01.
Pharmacological properties
Pharmacodynamics.
Amlodipine is 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.
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.
Dilation of the main coronary arteries and coronary arterioles (normal and ischemic) 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 reaching 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, and gout.
Pharmacokinetics.
Suction/distribution.
After oral administration in therapeutic doses, amlodipine is gradually absorbed into the blood plasma. The absolute bioavailability of the unchanged molecule is approximately 64-80%. Maximum plasma concentrations are reached 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%.
Concomitant food intake does not affect the absorption of amlodipine.
Metabolism/excretion.
The plasma half-life is approximately 35–50 hours. Steady-state plasma concentrations are reached after 7–8 days of systemic administration. Amlodipine is primarily metabolized to inactive metabolites. Approximately 60% of the administered dose is excreted in the urine, approximately 10% of which is unchanged amlodipine.
Elderly patients.
The time to reach steady-state plasma concentrations of amlodipine is similar in elderly and adult patients. The clearance of amlodipine is usually somewhat reduced, which in elderly patients leads to an increase in the area under the concentration-time curve (AUC) and the half-life of the drug.
Patients with impaired renal function.
Amlodipine is extensively biotransformed to inactive metabolites. 10% of amlodipine is excreted unchanged in the urine. The concentration of amlodipine in the blood plasma does 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 impaired liver function.
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%.
Children.
Pharmacokinetic studies were conducted in 74 hypertensive children aged 12 to 17 years (including 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) who received amlodipine at doses of 1.25–20 mg/day in 1 or 2 divided doses. Typically, oral clearance in children aged 6 to 12 years and 13 to 17 years was 22.5 and 27.4 l/h, respectively, for boys and 16.4 and 21.3 l/h, respectively, for girls. There is considerable inter-patient variability in exposure. Limited information is available in patients under 6 years of age.
Indication
Arterial hypertension.
Vasospastic angina (Prinzmetal's angina).
Contraindication
Known hypersensitivity to dihydropyridines, amlodipine or any other component of the drug.
Severe arterial hypotension.
Shock (including cardiogenic shock).
Left ventricular outflow tract obstruction (e.g. severe aortic stenosis).
Hemodynamically unstable heart failure after acute myocardial infarction.
Interaction with other medicinal products and other types of interactions
Effect of other drugs on amlodipine.
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 during in vitro studies with human blood plasma indicate that amlodipine has no effect on the binding of the studied drugs (digoxin, phenytoin, warfarin or indomethacin) to blood proteins.
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 and an increased risk of hypotension. The clinical significance of these 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.
There is no information on the effect of CYP3A4 inducers on amlodipine. Concomitant use of amlodipine and drugs that are CYP3A4 inducers (e.g. rifampicin, St. John's wort) may lead to a decrease in amlodipine plasma concentrations, therefore such combinations should be used with caution.
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.
The effect of amlodipine on other drugs.
The hypotensive effect of amlodipine potentiates the hypotensive effect of other antihypertensive agents.
Tacrolimus.
There is a risk of increased blood levels of tacrolimus when co-administered with amlodipine, but the pharmacokinetic mechanism of this interaction is not fully established. To avoid tacrolimus toxicity when co-administered with amlodipine, regular monitoring of tacrolimus blood levels and, if necessary, dosage adjustment are required.
Cyclosporine.
No interaction studies have been conducted with ciclosporin and amlodipine, except in renal transplant patients, where variable increases in residual ciclosporin concentrations were observed. Monitoring of ciclosporin concentrations and, if necessary, reduction of the ciclosporin dose should be considered in renal transplant patients receiving amlodipine.
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.
Amlodipine has been reported to have no effect on the pharmacokinetics of atorvastatin, digoxin, or warfarin.
No effect of amlodipine on laboratory test results was found.
Sildenafil.
A single dose of 100 mg of sildenafil in patients with essential hypertension did not affect the pharmacokinetics of amlodipine. When amlodipine and sildenafil were used simultaneously, each of the drugs exhibited an antihypertensive effect independently of the other.
Other medicines.
Clinical 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 did not affect 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.
It is not known whether amlodipine affects laboratory test results.
Application features
The safety and efficacy of amlodipine in hypertensive crisis have not been evaluated.
Amlodipine should be used with caution in this patient population. 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.
Patients with impaired liver function.
The half-life of amlodipine and AUC parameters are longer in patients with impaired liver function; there are no recommendations regarding the dosage of the drug. Therefore, this category of patients should start using the drug at 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 titration and careful monitoring of the patient's condition.
Patients with renal failure.
This category of patients should use the usual doses of the drug. The concentration of amlodipine in the blood plasma does not correlate with the degree of renal impairment. Amlodipine is not removed by dialysis.
Amlodipine does not affect the results of laboratory tests.
Elderly patients.
Increasing the dose of the drug in this category of patients should be done with caution.
Other
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.
Use during pregnancy or breastfeeding
Pregnancy.
The safety of amlodipine 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 pregnant woman and the fetus.
Reproductive toxicity was observed in animal studies at high doses.
Breastfeeding period.
It is not known whether amlodipine is excreted in human milk. A decision must be made whether to continue breastfeeding or to continue using amlodipine, taking into account the benefit of breastfeeding for the child and the benefit of the drug for the woman.
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.
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.
Method of administration and doses
For oral administration. The tablets should be taken with a glass of liquid (e.g. water), with or without food.
The break line is intended to help break the tablet for easier swallowing, not to divide it into two doses.
Adults.
For the treatment of hypertension and angina pectoris, the usual starting dose of amlodipine is 5 mg once daily. Depending on the patient's response to therapy, the dose may be increased to a maximum dose of 10 mg 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 of using the drug in combination with thiazide diuretics, alpha-blockers, beta-blockers or angiotensin-converting enzyme 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 angiotensin-converting enzyme inhibitors.
Children aged 6 years and older with arterial hypertension.
The recommended initial dose of amlodipine for this category of patients is 2.5 mg 1 time per day. If the desired blood pressure level is not achieved within 4 weeks, the dose can be increased to 5 mg per day. The use of the drug in doses higher than 5 mg in this category of patients has not been studied.
Elderly patients.
There is no need for dose adjustment for this category of patients. Increasing the dose should be done with caution.
Patients with renal impairment.
It is recommended to use the usual doses of the drug, since the concentration of amlodipine in the blood plasma is not related to the severity of renal failure. Amlodipine is not removed by dialysis.
Patients with impaired liver function.
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 the drug should be started with the lowest dose (see sections "Special instructions for use" and "Pharmacological properties. Pharmacokinetics"). The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. Patients with severe hepatic impairment should start with the lowest dose and gradually increase it.
The drug can be used in children aged 6 years and over.
It is not known how amlodipine affects blood pressure in patients under 6 years of age.
Overdose
Experience with intentional overdose of the drug is limited.
Symptoms: 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 shock with fatal outcome, has been reported.
Treatment: clinically significant arterial hypotension caused by amlodipine overdose requires active support of the cardiovascular system, including frequent monitoring of cardiac and respiratory functions, providing the patient with a horizontal position, raising the lower extremities, monitoring the volume of circulating fluid 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 highly protein bound, the effect of dialysis is negligible.
Adverse reactions
The most commonly reported adverse reactions with amlodipine are: drowsiness, dizziness, headache, palpitations, flushing, abdominal pain, nausea, leg swelling, edema, and fatigue.
Blood and lymphatic system disorders: leukocytopenia, thrombocytopenia.
On the part of the immune system: allergic reactions.
Metabolic and nutritional disorders: hyperglycemia.
Psychiatric disorders: depression, mood changes (including anxiety), insomnia, confusion.
Nervous system: drowsiness, dizziness, headache (mainly at the beginning of treatment), tremor, dysgeusia, syncope, hypoesthesia, paresthesia, hypertonicity, peripheral neuropathy.
On the part of the organs of vision: visual disturbances (including diplopia).
From the side of the organs of hearing and labyrinth: ringing in the ears.
Cardiovascular system: palpitations, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), myocardial infarction, hot flashes, hypotension, vasculitis.
Respiratory: dyspnea, cough, rhinitis.
Gastrointestinal: abdominal pain, nausea, dyspepsia, intestinal motility disorders (including diarrhea and constipation), vomiting, dry mouth, pancreatitis, gastritis, gingival hyperplasia.
Hepatobiliary system: hepatitis, jaundice, increased liver enzymes (most often associated with cholestasis).
Skin and subcutaneous tissue disorders: alopecia, purpura, skin discoloration, increased sweating, itching, rash, exanthema, urticaria, angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity.
Musculoskeletal and connective tissue disorders: leg swelling, muscle cramps, arthralgia, myalgia, back pain.
Renal and urinary disorders: urinary incontinence, nocturia, increased urinary frequency.
From the reproductive system and mammary glands: impotence, gynecomastia.
General disorders: edema, fatigue, asthenia, chest pain, pain, malaise.
Research: increase or decrease in body weight.
Exceptional cases of extrapyramidal syndrome have been reported.
Children.
The adverse reaction profile was similar to that observed in adults. The following adverse reactions were reported: headache, dizziness, vasodilation, epistaxis, abdominal pain, asthenia. Most adverse reactions were mild or moderate in severity.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after the registration of a medicinal product is important. This allows for continuous monitoring of the benefit-risk balance of the medicinal product. Physicians should report any suspected adverse reactions as required by law.
Expiration date
5 years.
Storage conditions
Store at a temperature not exceeding 25 °C. Store in the original packaging. Keep out of the reach of children.
Packaging
10 tablets in a blister; 3 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
JSC TEVA Pharmaceutical Plant.
Address
Precinct 1; H-4042 Debrecen, Pallagi Str. 13, Hungary.
