INSTRUCTION
for medical use of a medicinal product
AMLODIPINE SANDOZ®
(AMLODIPINE SANDOZ®)
Storage:
active substance: amlodipine; 1 tablet contains amlodipine 5 mg or 10 mg in the form of amlodipine besylate; auxiliary substances: sodium starch glycollate (type A), calcium anhydrous hydrophosphate, microcrystalline cellulose, magnesium stearate.
Medicinal form. Tablets.
Basic physical and chemical properties:
5 mg tablets: white or almost white oblong tablets with a front, one on one side and a label "5" on the other;
tablets of 10 mg: white or almost white oblong tablets with a front, one side and a "10" on the other.
Pharmacotherapeutic group.
Selective calcium antagonists with a predominant effect on the blood vessels. Code АТХ С08С А01.
Pharmacological properties.
Pharmacodynamics.
Amlodipine is an antagonist of calcium (a derivative of dihydropyridine), which blocks the flow of calcium ions to the myocardium and to the smooth muscle cells.
The mechanism of hypotensive action of amlodipine is due to a direct relaxing effect on the smooth muscle of the vessels. The exact mechanism of the anti-anginal effect of amlodipine is not sufficiently defined, but the following effects play a role:
- Amlodipine expands peripheral arterioles and thus reduces peripheral resistance (post-loading). Since the heart rate remains stable, reducing heart load leads to a decrease in energy consumption and myocardial oxygen demand;
- 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 enlargement enhances myocardial saturation with oxygen in patients with coronary artery spasm (angina pectoris or variant angina).
In patients with arterial hypertension, the use of the drug once a day provides a clinically meaningful reduction of blood pressure for 24 hours in the position both lying and standing. Because of the slow onset of amlodipine, acute arterial hypotension is usually not observed.
In patients with angina when applying one daily dose of the drug increases total physical activity, time to the onset of angina and time to 1 mm depression of the segment of ST. The drug reduces the incidence of angina and reduces the need for nitroglycerin.
Amlodipine is not associated with any adverse metabolic actions or changes in the level of lipids in blood plasma 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. Absolute bioavailability of the unchanged molecule is about 64-80%. The maximum plasma concentration is reached within 6-12 hours after application. The volume of distribution is approximately 21 l / kg; The dissociation constant of acid (pKa) amlodipine is 8.6. In vitro studies have shown that binding of amlodipine to plasma proteins is approximately 97.5%.
Simultaneous food intake does not affect the absorption of amlodipine.
Metabolism / withdrawal.
The half-life of blood plasma is about 35-50 hours. Equilibrium concentration in blood plasma is achieved after 7-8 days of continuous use of the drug. Amlodipine is mainly metabolized to the formation of inactive metabolites. About 60% of the administered dose is excreted in urine, about 10% of which is amlodipine in the unmodified form.
Older patients.
The time to achieve equilibrium concentrations of amlodipine in blood plasma is similar in elderly patients and in adult patients. The clearance of amlodipine is usually somewhat 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 impaired renal function.
Amlodipine is extensively biotransformed into inactive metabolites. 10% of amlodipine is excreted unchanged in the urine. Changes in the concentration of amlodipine in plasma do not correlate with the degree of renal dysfunction. For patients with impaired renal function, normal doses of amlodipine may be used. Amlodipine is not removed by dialysis.
Patients with impaired liver function.
Information on the use of amlodipine in patients with impaired liver function 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%.
Children.
The pharmacokinetics study was conducted on 74 children with hypertension from 12 to 17 years of age (also 34 patients aged 6 to 12 years old and 28 patients aged 13 to 17 years) who used amlodipine at doses of 1.25 to 20 mg per day for 1 or 2 receptions. Usually, oral clearance in children between the ages of 6 and 12 and from 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 a significant variation in exposure in different patients. Information about patients under the age of 6 years is limited.
Clinical characteristics.
Indication.
- Arterial hypertension.
- Chronic stable angina pectoris.
- Vasospastic angina (angina pectoris).
Contraindication.
There is a known hypersensitivity to dihydropyridines, amlodipine or to any other component of the drug. Arterial hypotension of severe severity. Shock (including cardiogenic shock). Obstruction of the left ventricular outflow tract (for example, severe aortic stenosis). Hemodynamically unstable cardiac insufficiency after acute myocardial infarction.
Interaction with other drugs and other types of interactions.
Effect of other drugs on amlodipine.
CYP3A4 inhibitors. Concomitant administration of amlodipine and potent or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungal agents, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) can lead to significant increases in amlodipine exposure, which may also increase the risk of hypotension. The clinical significance of such changes may be more pronounced in the elderly. Clinical monitoring of the patient's condition and dose selection may be necessary.
Inducers CYP3A4. No information is available on the effect of inducers of CYP3A4 on amlodipine. Simultaneous administration of amlodipine and CYP3A4 inducers (eg rifampicin, St. John's wort) may lead to a decrease in the plasma amlodipine levels of amlodipine; therefore, such combinations should be used with caution.
It is not recommended to use amlodipine at the same time and to use grapefruit or grapefruit juice, since in some patients the bioavailability of amlodipine may increase, which in turn leads to increased antihypertensive effects.
Dantrolene (infusion). Animals experienced ventricular fibrillation with fatal outcome and cardiovascular collapse caused by hyperkalaemia after intravenous administration of verapamil and dantrolen. Due to the risk of developing hyperkalaemia, it is recommended that concomitant use of calcium channel blockers such as amlodipine, predisposing malignant hyperthermia to patients and in the treatment of malignant hyperthermia is avoided.
Effect of amlodipine on other medicines.
Hypotensive effect of amlodipine increases the antihypertensive effect of other antihypertensive drugs. Investigations of drug interaction have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, warfarin.
Tacrolimus There is a risk of rising levels of tacrolimus in the blood while co-administered with amlodipine, but the pharmacokinetic mechanism of such interaction is not fully established. To avoid the toxicity of tacrolimus, with the co-administration of amlodipine, regular monitoring of tacrolimus blood levels and, if necessary, dose adjustment is required.
Ciclosporin. For renal transplant patients using amlodipine, monitoring of cyclosporin concentrations and, if necessary, lowering the dose of cyclosporine should be considered.
Simvastatin Simultaneous administration of multiple doses of 10 mg of amlodipine and 80 mg of simvastatin results in an increase in 77% of the exposure to simvastatin compared with the administration of simvastatin alone. Limitations of doses of simvastatin in patients taking amlodipine are 20 mg per day.
Application features.
The safety and efficacy of amlodipine in hypertensive crisis has not been evaluated.
Patients with heart failure.
This patient category of amlodipine should be used with caution. There is evidence of an increase in the incidence of pulmonary edema in patients with severe heart failure (class III and IV according to NYHA classification) when amlodipine is used. 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 impaired liver function.
The half-life of amlodipine and AUC are higher in patients with impaired liver function; There are no recommendations for the doses of the drug. Therefore, this category of patients should start using the drug from 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 dosing and careful monitoring of the patient's condition.
Older patients.
Increase the dose of the drug in this category of patients should be taken 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 blood plasma do not correlate with the degree of renal impairment. 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, since in some patients, bioavailability may be increased, which will increase the hypotensive effect of the drug.
Use during pregnancy or breastfeeding.
The safety of amlodipine has not been established in women during pregnancy.
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 exceeds the potential harm of maternal and fetal care.
During reproductive toxicity, animal studies have shown reproductive toxicity when administered at high doses.
Breast feeding period.
It is not known whether amlodipine penetrates into breast milk. When deciding whether to continue lactation or on the use of amlodipine, it is important to assess the benefits of breastfeeding for the child and the benefits of using the drug for the mother.
Fertility.
Reversible biochemical changes in the sperm head in some patients have been reported with calcium channel blockers. Clinical information on the potential effects of amlodipine on fertility is not enough.
Ability to influence the reaction speed while driving or other mechanisms.
Amlodipine may have minor or moderate effects on the ability to drive vehicles or work with other mechanisms. The rate of response can be reduced by the presence of symptoms such as dizziness, headache, confusion or nausea.
Care should be taken, especially at the beginning of therapy.
Method of administration and dose.
Adults
For the treatment of arterial hypertension and angina, the usual initial dose of the drug is 5 mg once a day. Depending on the patient's response to therapy, the dose may be increased to a maximum dose of 10 mg once daily.
Patients with angina pectoris can be used as monotherapy or in combination with other antianginal drugs for resistance to nitrates and / or adequate doses of beta-blockers.
There is experience with the use of 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 select the doses of the drug while co-administered with thiazide diuretics, beta-blockers, and angiotensin converting enzyme inhibitors.
Children aged 6 years and older with hypertension.
The recommended starting dose for this category of patients is 2.5 mg once a day. If the required blood pressure level is not reached within 4 weeks, the dose can be increased to 5 mg per day. The use of dasg in doses above 5 mg for this category of patients has not been studied.
Tablets of 5 mg and 10 mg are for distribution in half for a dose of 2.5 mg and 5 mg respectively.
Older patients.
There is no need to select a dose for this category of patients. The dose increase should be done with caution.
Patients with impaired renal function.
It is recommended to use regular doses of the dasg, since changes in the concentration of amlodipine in the blood plasma are not related to the severity of renal failure. Amlodipine is not eliminated by dialysis.
Use in patients with hepatic insufficiency.
The doses of the drug for use in patients with mild to moderate hepatic insufficiency have not been established, so the dose selection should be done with caution and start using at the lowest dose (see sections "Peculiarities of use" and "Pharmacokinetics").
Children.
The drug is for use in children aged 6 years and older.
The effect of amlodipine on arterial pressure in patients under the age of 6 years is unknown.
Overdose
The experience of intentional overdose of the drug is limited.
Symptoms: The available information suggests that a significant overdose of amlodipine will result in excessive peripheral vasodilation and, possibly, reflex tachycardia. Significant and possibly prolonged systemic arterial 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 functions, lifting of the lower extremities, monitoring of the volume of circulating fluid and urination.
Vascular tone and blood pressure can be used to restore vasoconstrictive drugs, making sure that there are no contraindications to their use. The use of intravenous gluconate calcium 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 charcoal for healthy volunteers within 2 hours after the administration of 10 mg of amlodipine significantly reduced its absorption.
Since amlodipine is highly bound to blood proteins, the effect of dialysis is negligible.
Adverse reactions.
When amlodipine was used, the following side effects were reported most often: drowsiness, dizziness, headache, palpitation, tides, abdominal pain, nausea, edema of the legs, swelling and fatigue.
Side effects reported during the treatment with amlodipine are listed below by system and grade of organs and at the frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to <1 10="" infrequent="" 1="" 1000="" -="" 100="" rarely="" 10000="" very="" br="">
From the blood and lymphatic system: very rarely - leukocytopenia, thrombocytopenia.
From the immune system: very rarely - allergic reactions.
Disorders of metabolism and alimentary disorders: very rarely - hyperglycemia.
Mental disorders: infrequent - insomnia, mood changes (including anxiety), depression; rarely - confusion of consciousness.
From the nervous system: often - drowsiness, dizziness, headache (mainly at the beginning of treatment); Uncommon - tremor, dysgeusia, syncope, hypesthesia, paresthesia; very rarely - hypertonum, peripheral neuropathy.
From the side of the vision: often - vision impairment (including diplopia).
From the organs of the ear and the labyrinth: infrequently - a bell in the ears.
From the side of the heart: often - an enlarged heartbeat; Uncommon - arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation); very rarely - myocardial infarction.
From the vessels: often - tides; Uncommon - arterial hypotension; very rarely - vasculitis.
Respiratory, thoracic and mediastinal disorders: often - dyspnea; Uncommon - rhinitis, cough.
From the gastrointestinal tract: often - abdominal pain, nausea, dyspepsia, peristalsis of the intestine (including constipation and diarrhea); Uncommon - vomiting, dry mouth; very rarely - pancreatitis, gastritis, gingival hyperplasia.
From the hepatobiliary system: very rare - hepatitis, jaundice, increased liver enzymes (most often associated with cholestasis).
From the skin and subcutaneous tissue: infrequently - alopecia, purpura, change in skin color, increased sweating, itching, rash, exanthema, urticaria; very rarely - angioneurotic edema, multivariate erythema, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity.
From the musculoskeletal and connective tissue: often - swelling of the legs, muscle cramps; Uncommon - arthralgia, myalgia, back pain.
On the part of the kidneys and the urinary tract: infrequently - urination failure, nocturia, increased frequency of urination.
From the reproductive system and mammary glands: infrequent - impotence, gynecomastia.
General disorders: very common - edema; often - increased fatigue, asthenia; Uncommon - pain for thrush, pain, malaise.
Research: infrequent - increase or decrease in body weight.
Exceptional cases of extrapyramidal syndrome were reported.
Notification of suspected adverse reactions.
Reporting suspected adverse reactions after the registration of a medicinal product is important. This enables continuous monitoring of the relationship between benefit and risks associated with the use of this drug. Doctors should report any suspected adverse reactions in accordance with legal requirements.
Expiration date. 3 years.
Storage conditions.
Store at a temperature not exceeding 25 ° C in original packaging to protect from light and moisture.
Keep out of the reach of children.
Packaging.
15 tablets in the blister; 2 (15 '2) blisters in a cardboard box.
Category of departure. By prescription.
Producer.
Lek Pharmaceutical Company D.D., Slovenia / Lek Pharmaceuticals d. d., Slovenia (responsible for issuing a series).
Location of the manufacturer and its address of the place of the activity.
Verevskova 57, Ljubljana 1526, Slovenia / Verovskova 57, 1526 Ljubljana, Slovenia.
