Instructions Amlodipine Sandoz tablets 5 mg blister No. 30
Composition
active ingredient: amlodipine;
1 tablet contains 5 mg amlodipine in the form of amlodipine besylate;
excipients: sodium starch glycolate (type A), calcium hydrogen phosphate anhydrous, microcrystalline cellulose, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties:
5 mg tablets: white or almost white oblong tablets with a bevel, a score on one side and marking "5" 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 expenditure and myocardial oxygen demand; dilation of the main coronary arteries and coronary arterioles (normal and ischemic) may also play a role in the mechanism of action of amlodipine. This 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, 1 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. 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 continuous 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. Changes in plasma amlodipine concentrations do not correlate with the degree of renal impairment. Patients with renal impairment can be treated with normal doses of amlodipine. Amlodipine is not dialysable.
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. The mean 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. 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). Obstruction of the outflow tract of the left ventricle (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 (NSAIDs), 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 result in a significant increase in amlodipine exposure, which may also lead to 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 simultaneously with grapefruit or grapefruit juice, 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 due to hyperkalemia have been observed in animals following intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, it is recommended that concomitant use of 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 increases the hypotensive effect of other antihypertensive agents. Drug interaction studies have shown that 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 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.
mTOR inhibitors (mammalian target of rapamycin).
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 with 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 10 mg amlodipine and 80 mg simvastatin resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. The dose limit for simvastatin in patients taking amlodipine is 20 mg daily.
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 as combination therapy, each drug had an independent hypotensive effect.
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.
Amlodipine should be used with caution in this patient population. There is evidence of an increased incidence of pulmonary edema in patients with severe heart failure (NYHA class III and IV) treated with amlodipine. 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 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 failure.
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. Reactions may be impaired if symptoms such as dizziness, headache, confusion or nausea occur.
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.
Reproductive toxicity was observed in animal studies at high doses.
Breastfeeding. Amlodipine is excreted in human milk. The amount of amlodipine that can reach the infant in breast milk may be 3-7 to 15% of the dose administered by the mother. The effects of amlodipine on the infant are unknown. A decision on whether to continue breastfeeding or to continue using amlodipine should be made taking into account the benefit of breastfeeding for the infant and the benefit of using the drug for the mother.
Fertility: Reversible biochemical changes in the sperm head have been reported in some patients receiving calcium channel blockers. There is insufficient clinical information regarding 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 is 5 mg once daily. Depending on the patient's response to therapy, the dose may be increased to a maximum 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 in using the drug in patients with arterial hypertension in combination with thiazide diuretics, alpha-blockers, beta-blockers or angiotensin-converting enzyme inhibitors.
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 for this category of patients is 2.5 mg once daily. If the desired blood pressure level is not achieved within 4 weeks, the dose can be increased to 5 mg daily. The use of the drug in doses higher than 5 mg in this category of patients has not been studied.
The 5 mg and 10 mg tablets are intended to be split in half to obtain doses of 2.5 mg and 5 mg, respectively.
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 insufficiency.
The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. In such patients, amlodipine should be started at the lowest dose and titrated gradually.
Children
The drug can be used in children aged 6 years and over.
The effect of amlodipine on blood pressure in patients under 6 years of age is unknown.
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 hypotension due to amlodipine overdose requires active support of the cardiovascular system, including frequent monitoring of cardiac and respiratory functions, 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 highly protein bound, the effect of dialysis is negligible.
Adverse reactions
The following adverse reactions were most commonly reported with amlodipine: drowsiness, dizziness, headache, palpitations (rapid heartbeat), hot flashes, abdominal pain, nausea, leg swelling, edema, and fatigue.
Adverse reactions reported with amlodipine are listed below by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, ≤ 1/100), rare (≥ 1/10,000, ≤ 1/1,000), very rare (≤ 1/10,000), not known (cannot be estimated from available data).
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 - insomnia, mood changes (including anxiety), depression; 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.
On the part of the organs of vision: often - visual disturbances (including diplopia).
From the side of the organs of hearing and labyrinth: infrequently - tinnitus.
Cardiac disorders: common: palpitations; uncommon: arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation); very rare: myocardial infarction.
Vascular disorders: often - hot flashes; infrequently - arterial hypotension; very rarely - vasculitis.
Respiratory, thoracic and mediastinal disorders: common: dyspnea; uncommon: rhinitis, cough.
Gastrointestinal: often - abdominal pain, nausea, dyspepsia, intestinal motility disorders (including constipation and diarrhea); 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: uncommon - alopecia, purpura, skin discoloration, increased sweating, itching, rash, exanthema, urticaria; very rare - angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity, unknown (cannot be estimated from the available data) - 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.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after a medicinal product has been authorised 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
3 years.
Storage conditions
Store at a temperature not exceeding 25 °C in the original packaging to protect from light and moisture.
Keep out of reach of children.
Packaging
15 tablets in a blister; 2 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Lek Pharmaceutical Company Ltd. (responsible for the release of the series).
Location of the manufacturer and its business address
Verovškova 57, Ljubljana 1526, Slovenia.
