Instructions for use Amlodipine-Teva tablets 5 mg blister No. 30
Composition
active ingredient: amlodipine;
1 tablet contains 5 mg or 10 mg of amlodipine (as amlodipine besylate);
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 side;
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 side.
Pharmacotherapeutic group
Drugs affecting the cardiovascular system. Selective calcium antagonists with a predominant effect on blood vessels. Dihydropyridine derivatives. Amlodipine. ATC code C08C A01.
Pharmacological properties
Pharmacodynamics.
Amlodipine is a calcium antagonist (dihydropyridine derivative) that blocks the transmembrane influx of calcium ions into myocardial and vascular smooth muscle.
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 has not been definitively determined, however, amlodipine reduces the total ischemic load due to the following effects.
Amlodipine dilates peripheral arterioles and thus reduces total peripheral resistance (afterload). Since the heart rate does not change, the reduction in 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).
Clinical efficacy and safety.
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 metabolic side 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 well absorbed with peak plasma concentrations (Cmax) occurring within 6–12 hours after dosing. The absolute bioavailability of the unchanged molecule is approximately 64–80%. The volume of distribution is approximately 21 l/kg, and 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 bioavailability of amlodipine.
Metabolism/excretion.
The terminal half-life of plasma elimination is approximately 35–50 hours and corresponds to once-daily dosing. Steady-state plasma concentrations are reached after 7–8 days of systemic administration. Amlodipine is primarily metabolized in the liver 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 patients. 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 half-life of the drug. The increase in AUC and half-life in patients with congestive heart failure was consistent with the age characteristics of the study group of patients.
Patients with renal impairment.
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 dialysable.
Patients with liver dysfunction.
Information on the use of amlodipine in patients with hepatic impairment is very limited. In patients with hepatic impairment, the clearance of amlodipine is reduced, resulting in a prolonged half-life and an increase in AUC by approximately 40-60%.
A population pharmacokinetic study was 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 to 20 mg/day in 1 or 2 divided doses. Typically, oral clearance (CL/F) 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.
Chronic stable angina.
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 safety data available for the use of amlodipine with thiazide diuretics, alpha-blockers, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, long-acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and oral hypoglycemic drugs.
In vitro data from human plasma studies 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 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.
Clarithromycin is an inhibitor of CYP3A4. Patients receiving clarithromycin and amlodipine concomitantly are at increased risk of hypotension. Close monitoring of patients is recommended when amlodipine and clarithromycin are co-administered.
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 fluctuate following concomitant use of known CYP3A4 inducers. Therefore, blood pressure monitoring and dose adjustment should be considered 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.
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, adjustment of tacrolimus dosage are required.
Mammalian target of rapamycin (mTOR) inhibitors.
mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When amlodipine is used concomitantly with mTOR inhibitors, it may potentiate the effects of the latter.
Cyclosporine.
Interaction studies of cyclosporine and amlodipine have not been conducted in healthy volunteers or other populations, except in renal transplant patients, where a variable increase in cyclosporine trough concentrations (mean 0-40%) was observed. In renal transplant patients receiving amlodipine, monitoring of cyclosporine concentrations should be considered and, if necessary, a reduction in the cyclosporine dose.
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.
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 had an independent hypotensive effect.
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.
Patients with heart failure.
Amlodipine should be used with caution in this patient population. In a long-term placebo-controlled study in patients with severe heart failure (NYHA functional class III-IV), the incidence of pulmonary edema was higher with amlodipine than with placebo. 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 liver dysfunction.
The half-life of amlodipine and AUC parameters are longer in patients with impaired liver function; there are no recommendations for dosage. 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 impairment.
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.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially 'sodium-free'.
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.
In animal studies, reproductive toxicity was observed at high doses.
Breastfeeding period.
Amlodipine is excreted in human milk. The ratio of the dose received by the newborn from the mother is estimated in the interquartile range to be 3-7%, with a maximum of 15%. The effect of amlodipine on the infant 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 weighed.
Fertility.
Reversible biochemical changes in the head of sperm have been reported in some patients receiving calcium channel blockers. There is insufficient clinical information regarding the potential effects of amlodipine on fertility. In one study, impaired fertility was observed in male rats.
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 tablet can be divided into equal doses.
If your doctor has prescribed ½ (half) tablet daily, do not use any tablet-splitting devices. Use the following instructions:
place the tablet on a flat, hard surface (e.g., table or countertop) with the embossed side up;
Break the tablet by pressing with the index fingers of both hands along the break line.
Adults.
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.
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.
When used in similar doses, amlodipine is equally well tolerated by elderly and younger patients. It is recommended that elderly patients be given the usual dose of the drug, but 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 liver dysfunction.
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 at the lowest dose (see sections "Pharmacological properties. Pharmacokinetics" and "Special instructions for use"). 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.
Children
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.
Non-cardiogenic pulmonary edema has been reported rarely following amlodipine overdose, which may be delayed in onset (24-48 hours after ingestion) and may require mechanical ventilation. Early resuscitation measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.
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.
Side effects
The most commonly reported adverse reactions with amlodipine are: drowsiness, dizziness, headache, palpitations, flushing, abdominal pain, nausea, leg swelling, oedema and fatigue. Adverse reactions reported with amlodipine treatment are listed below with the following frequencies: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency unknown (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Blood and lymphatic system disorders: very rarely – leukocytopenia, thrombocytopenia.
On the part of the immune system: very rarely - allergic reactions.
Metabolism and nutritional disorders: very rarely - hyperglycemia.
Psychiatric disorders: infrequently - depression, mood changes (including anxiety), insomnia; rarely - confusion.
Nervous system: often - drowsiness, dizziness, headache (mainly at the beginning of treatment); infrequently - tremor, dysgeusia, syncope, hypoesthesia, paresthesia; very rarely - hypertonicity, peripheral neuropathy; frequency unknown - extrapyramidal disorders.
On the part of the organs of vision: often - visual disturbances (including diplopia).
Cardiovascular system: often - palpitations, hot flashes; infrequently - arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), arterial hypotension; very rarely - myocardial infarction, vasculitis.
From the respiratory system: often - dyspnea; infrequently - cough, rhinitis.
Gastrointestinal: often - abdominal pain, nausea, dyspepsia, intestinal motility disorders (including diarrhea and constipation); infrequently - vomiting, dry mouth; very rarely - pancreatitis, gastritis, gingival hyperplasia.
Hepatobiliary system: very rarely - hepatitis, jaundice, increased liver enzymes (most often associated with cholestasis).
Skin and subcutaneous tissue disorders: infrequently - alopecia, purpura, skin discoloration, increased sweating, itching, rash, exanthema, urticaria; very rarely - angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity; frequency unknown - toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: common: leg swelling, muscle cramps; uncommon: arthralgia, myalgia, back pain.
Renal and urinary disorders: uncommon – urinary disorders, nocturia, increased urinary frequency.
From the reproductive system and mammary glands: infrequently - impotence, gynecomastia.
General disorders: very often - edema; often - fatigue, asthenia; infrequently - chest pain, pain, malaise.
Investigations: uncommon – weight gain or weight loss.
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. All cases of suspected adverse reactions and lack of efficacy of the drug should be reported via the link: https://aisf.dec.gov.ua/.
Expiration date
5 years.
Storage conditions
Store at a temperature not exceeding 25 °C. Store in the original packaging. Keep the blister in the cardboard box. Keep out of the reach of children.
Packaging
10 tablets in a blister; 3 or 9 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Teva Pharmaceutical Plant JSC.
Location of the manufacturer and address of its place of business.
Precinct 1; H-4042 Debrecen, Pallagi Str. 13, Hungary.
