Description
Release form
tablets.
Packing
30 pcs.
Pharmacological action
Pharmacotherapeutic group: BMCC
Pharmacological action
Combined antihypertensive drug. It has pronounced antihypertensive and antianginal effects due to the complementary action of two active substances: slow calcium channel blocker (BMCC) – amlodipine and selective beta1-blocker – bisoprolol.
Amlodipine
Amlodipine blocks calcium channels, reduces the transmembrane transition of calcium ions to the cell (more to the smooth muscle cells of blood vessels than to cardiomyocytes).
The antihypertensive effect of amlodipine is due to the direct relaxing effect on vascular smooth muscle cells, which leads to a decrease in peripheral vascular resistance.
The mechanism of antianginal action is not fully understood, perhaps it is associated with the following two effects.
1. The expansion of peripheral arterioles reduces OPSS, ie afterload. Since amlodipine does not cause reflex tachycardia, myocardial energy and oxygen consumption is reduced.
2. The expansion of the large coronary arteries and coronary arterioles improves the oxygen supply of both normal and ischemic myocardial zones. Thanks to these effects, myocardial oxygen supply improves, even with spasm of the coronary arteries (Prinzmetal angina pectoris or unstable angina pectoris).
In patients with arterial hypertension, taking the drug 1 time / day causes a clinically significant decrease in blood pressure when lying and standing throughout the entire 24-hour interval between doses of the drug. Due to the slow development of the antihypertensive effect of amlodipine, it does not cause acute arterial hypotension.
In patients with angina pectoris, taking the drug 1 time / day increases the total time it takes to exercise, the time before the development of an attack of angina pectoris, and also time to a significant reduction in the ST interval, and also reduces the frequency of angina attacks and the need for sublingual administration of nitroglycerin.
No adverse effects of amlodipine on the exchange of plasma lipids, blood glucose and uric acid of blood serum.
Bisoprolol
Bisoprolol is a selective beta1-blocker, without its own sympathomimetic activity, does not have a membrane-stabilizing effect.
It has only a slight affinity for the c2-adrenergic receptors of the smooth muscles of the bronchi and blood vessels, as well as for the 2 -adrenergic receptors involved in the regulation of metabolism. Consequently, bisoprolol as a whole does not affect airway resistance and metabolic processes in which β2-adrenergic receptors are involved.
The selective effect of the drug on 1-adrenergic receptors remains beyond the therapeutic range.
Bisoprolol does not have a pronounced negative inotropic effect.
The maximum effect of the drug is achieved 3-4 hours after ingestion. Even with the appointment of bisoprolol 1 time / day, its therapeutic effect persists for 24 hours thanks to 10-12 hours of T1 / 2 from blood plasma. As a rule, the maximum antihypertensive effect is achieved 2 weeks after the start of treatment.
Bisoprolol reduces the activity of the sympathoadrenal system (CAS) by blocking 1-adrenoreceptors of the heart.
With a single oral administration in patients with coronary heart disease without signs of chronic heart failure, bisoprolol reduces heart rate, reduces stroke volume of the heart and, as a result, reduces ejection fraction and myocardial oxygen demand. With prolonged therapy, initially elevated OPSS decreases. A decrease in plasma renin activity is considered as one of the components of the hypotensive effect of beta-blockers.
Pharmacokinetics
Amlodipine
Absorption
Amlodipine is well absorbed after oral administration. Cmax in blood plasma is noted after 6-12 hours. Taking the drug with food does not affect its absorption. Absolute bioavailability is 64-80%.
Distribution of
Visible Vd is 21 l / kg. Css in blood plasma (5-15 ng / ml) is achieved 7-8 days after the start of the drug.
In vitro studies have shown that circulating amlodipine is approximately 93-98% bound to plasma proteins.
Metabolism and excretion
Amlodipine undergoes extensive metabolism in the liver. Approximately 90% of the dose taken is converted to inactive pyridine derivatives. About 10% of the dose taken is excreted unchanged in the urine. Approximately 60% of the amount of inactive metabolites is excreted by the kidneys and 20-25% through the intestines. The decrease in plasma concentration is biphasic. The final T1 / 2 is approximately 35-50 hours, which allows the drug to be administered 1 time / day. The total clearance is 7 ml / min / kg (25 l / h in a patient weighing 60 kg). In elderly patients, it is 19 l / h.
Pharmacokinetics in special clinical cases
No significant changes in the pharmacokinetics of amlodipine were observed in elderly patients or patients with renal failure.
Due to decreased clearance, patients with hepatic insufficiency should be given a lower initial dose.
bisoprolol
Absorption
bisoprolol is almost completely absorbed (more than 90%) from the digestive tract. Its bioavailability due to insignificant metabolism during the first passage through the liver (at the level of about 10%) is about 90%
after oral administration. Eating does not affect bioavailability. Bisoprolol demonstrates linear kinetics, and its plasma concentrations are proportional to the dose taken in the range from 5 to 20 mg. Cmax in plasma is reached after 2-3 hours.
Distribution of
Bisoprolol is distributed quite widely. Vd is 3.5 l / kg. Binding to plasma proteins reaches approximately 30%.
Metabolism
Metabolized via the oxidative pathway without subsequent conjugation. All metabolites are polar (water soluble) and excreted by the kidneys. The main metabolites found in blood plasma and urine do not show pharmacological activity. The data obtained as a result of experiments with human liver microsomes in vitro show that bisoprolol is metabolized primarily by the isoenzyme CYP3A4 (about 95%), and the isoenzyme CYP2D6 plays only a minor role.
Excretion
Bisoprolol clearance is determined by the balance between excretion of the kidneys unchanged (about 50%) and metabolism in the liver (about 50%) to metabolites that are also excreted by the kidneys. The total clearance is 15 l / h. T1 / 2-10-12 hours
Indications
Arterial hypertension: replacement of therapy with monocomponent preparations of amlodipine and bisoprolol in the same doses.
Contraindications
For amlodipine: unstable angina (except for Prinzmetal angina)
acute myocardial infarction (within the first 28 days)
clinically significant aortic stenosis.
For bisoprolol: acute heart failure or chronic heart failure (CHF) in the decompensation stage, requiring inotropic therapy
atrioventricular (AV) block II and III degree, without pacemaker
sinus node weakness syndrome (SSS)
sinoatrial blockade
severe bradycardia (heart rate less than 60 beats / min)
severe forms of bronchial asthma or chronic obstructive pulmonary disease (COPD)
severe rheumatic syndromes simultaneous use of alpha-blockers)
metabolic acidosis
Amlodipine / bisoprolol combination: hypersensitivity to amlodipine, other derivatives of dihydride ropiridine, bisoprolol and / or any of the excipients
severe arterial hypotension (systolic blood pressure less than 100 mm Hg)
shock (including cardiogenic)
children under 18 years of age (efficacy and safety not established)
Caution
CHF (including non-ischemic etiology of functional class III-IV according to NYHA classification), liver failure, renal failure, hyperthyroidism, diabetes mellitus with significant fluctuations in the concentration of glucose in the blood, AV block I degree, Prinzmetal angina, peripheral arterial occlusion diseases, psoriasis (including history), starvation (strict diet), pheochromocytoma (with the use of alpha-ad enoblokatorov), bronchial asthma and COPD simultaneously conducted desensitizing therapy, general anesthesia, advanced age, hypotension, type 1 diabetes, aortic stenosis, mitral stenosis, acute myocardial infarction (after 28 days).
Use during pregnancy and lactation
Amlodipine:
In experimental studies, the fetotoxic and embryotoxic effects of the drug have not been established, but use during pregnancy is possible only if the benefit to the mother outweighs the potential risk to the fetus.
There is no evidence of excretion of amlodipine in breast milk. However, it is known that other BMCC – derivatives of dihydropyridine, are excreted in breast milk. In this connection, if necessary, the appointment of amlodipine during lactation should decide on the termination of breastfeeding.
For bisoprolol:
The use of bisoprolol during pregnancy is possible only when the intended benefits to the mother outweigh the potential risk to the fetus. Beta-blockers reduce blood flow in the placenta and can affect fetal development. Blood flow in the placenta and uterus should be monitored, as well as the growth and development of the unborn child, and in case of adverse events regarding pregnancy and / or the fetus, take alternative methods of therapy.
The newborn should be carefully examined after childbirth. In the first three days of life, symptoms of bradycardia and hypoglycemia may occur. There is no data on the release of bisoprolol into breast milk. Therefore, its intake is not recommended for women during breastfeeding. If bisoprolol is required during lactation, breast-feeding should be discontinued.
Special instructions
For amlodipine:
Patients with heart failure should take amlodipine with caution. In patients with heart failure stage III-IV according to NYHA classification, amlodipine increases the risk of pulmonary edema, which is not associated with an aggravation of symptoms of chronic heart failure.
For bisoprolol:
Discontinuation of bisoprolol treatment should not be sudden, especially in patients with coronary artery disease, unless there is a clear indication for drug withdrawal. Sudden withdrawal of bisoprolol can lead to a temporary deterioration of cardiac pathology.
Bisoprolol should be prescribed with extreme caution to patients with arterial hypertension or angina pectoris, combined with heart failure.
As with other beta-blockers, bisoprolol can cause increased sensitivity to allergens and increased anaphylactic reactions, so caution should be exercised with simultaneous desensitizing therapy. The use of adrenaline may not always give the expected therapeutic effect.
When using bisoprolol, the symptoms of hyperthyroidism may mask.
In patients with pheochromocytoma, bisoprolol should be prescribed only after blocking alpha-adrenergic receptors.
Before general anesthesia is performed, the anesthetist must be informed that the patient is taking beta-blockers. If beta-blocker must be withdrawn before surgery, this should be done gradually and completed approximately 48 hours before anesthesia.
In bronchial asthma or COPD, the simultaneous use of bronchodilating agents is indicated. In patients with bronchial asthma, an increase in airway resistance is possible, which requires a higher dose of beta2-adrenergic agonists.
Composition
1 tab.
bisoprolol fumarate 5 mg
amlodipine besilate 6.95 mg,
which corresponds to the content of amlodipine 5 mg
Excipients: microcrystalline cellulose – 130.55 mg, sodium carboxymethyl starch (type A) – 5 mg, 1 mg magnesium stearate – mg
Dosage and Administration
Tablets for oral administration. Tablets should be taken in the morning, regardless of food intake, without chewing.
Recommended daily dosage is 1 tablet per day for a specific dosage.
Selection and titration of a dose individually for each patient is carried out by a doctor during the appointment of monocomponent preparations containing the active ingredients that make up the Concor AM preparation.
Duration of treatment
Treatment with Concor AM is usually a long-term therapy.
Impaired liver function
In patients with impaired liver function, amlodipine excretion may be slowed down. A special dosage regimen for this group of patients is not defined, but the drug in this case should be prescribed with caution.
For patients with severely impaired liver function, the maximum daily dose of bisoprolol is 10 mg.
Impaired renal function
Patients with impaired renal function of mild or moderate severity of dosage regimen are usually not required. Amlodipine is not excreted by dialysis. Dialysis patients should be given amlodipine with extreme caution.
For patients with severe renal impairment (creatinine clearance (CC) less than 20 ml / min), the maximum daily dose of bisoprolol is 10 mg.
Elderly patients
Elderly patients may be given normal doses of the drug. Caution is required only with increasing doses.
Children
The drug is not recommended for use in children under the age of 18 due to the lack of data on efficacy and safety.
Treatment should not be abruptly discontinued, as this may lead to a temporary worsening of the clinical condition. Especially treatment should not be abruptly discontinued in patients with coronary artery disease. A gradual dose reduction is recommended.
Side effects
Undesirable side reactions observed when using the active ingredients separately, presented according to the following criteria for frequency grouping:
Very frequent> 1/10 frequent> 1/100 -> 1/1000 -> 1/10 000 – For amlodipine: Disorders of the blood and lymphatic system: very rare: leukopenia thrombocytopenia.
Immune system disorders: very rare: allergic reactions.
Metabolism and nutritional disorders: very rare: hyperglycemia.
Mental disorders: infrequently: insomnia, mood changes (including anxiety), depression rarely: confusion.
Disorders of the nervous system: often: headache, dizziness, drowsiness (especially at the beginning of treatment) infrequently: fainting, hypesthesia, paresthesia, dysgeusia, tremor very rarely: muscle hypertension, peripheral neuropathy.
Disorders of the organ of vision: infrequently: visual impairment (including diplopia).
Hearing impairment and labyrinth disorders: infrequently: tinnitus.
Disorders of the gastrointestinal tract: often: nausea, abdominal pain infrequently: vomiting, change in bowel movement (including constipation or diarrhea), dyspepsia, dry oral mucosa very rarely – gastritis, gingival hyperplasia, pancreatitis .
Disorders of the liver and biliary tract: very rare: hepatitis *, jaundice *.
Disorders from the heart: often: palpitations very rare: myocardial infarction, arrhythmia (bradycardia, ventricular tachycardia, atrial fibrillation).
Vascular disorders: often: flushing of the face, infrequently: marked decrease in blood pressure is very rare: vasculitis.
Disorders of the respiratory system, chest and mediastinal organs: infrequently: shortness of breath, rhinitis is very rare: cough.
Disorders of the kidneys and urinary tract: infrequently: pollakiuria, painful urination, nocturia.
Disorders of the genitals and mammary gland: infrequently: impotence, gynecomastia.
General disorders and disorders at the injection site: often: peripheral edema, increased fatigue infrequently: chest pain, asthenia, pain, general malaise.
Disorders of the musculoskeletal and connective tissue: often: ankle swelling infrequently: arthralgia, myalgia, muscle cramps, back pain.
Disorders of the skin and subcutaneous integument: infrequently: alopecia, purpura, skin discoloration, increased sweating, itching, rash, exanthema very rarely: angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke’s edema, photosensitivity.
Laboratory and instrumental data: infrequently: increase in body weight, decrease in body weight is very rare: increase in the activity of “liver” enzymes *.
* In most cases with cholestasis
For bisoprolol:
Disorders in the metabolism and nutrition: rarely: increased concentration of triglycerides.
Mental disorders: infrequently: depression seldom: hallucinations, nightmares.
Disorders of the nervous system: often: headache **, dizziness ** infrequently: insomnia rarely: fainting.
Disorders of the organ of vision: rare: decreased lacrimation (should be considered when wearing contact lenses) very rarely: conjunctivitis.
Hearing impairment and labyrinth disorders: rarely: hearing impairment.
Disturbances from the heart: infrequently: violation of AV conduction, bradycardia, aggravation of symptoms of chronic heart failure.
Vascular disorders: often: cold or numbness in limbs, marked decrease in blood pressure infrequently: orthostatic hypotension.
Disorders of the respiratory system, chest and mediastinal organs: infrequently: bronchospasm in patients with bronchial asthma or a history of airway obstruction rarely: allergic rhinitis.
Disorders of the gastrointestinal tract: often: nausea, vomiting, diarrhea, constipation.
Disorders of the liver and biliary tract: rarely: hepatitis.
Disorders of the skin and subcutaneous integument: rarely: hypersensitivity reactions such as pruritus, rash, redness of the skin very rarely: alopecia. Beta-blockers can exacerbate the symptoms of psoriasis or cause a psoriasis-like rash.
Disorders of the musculoskeletal and connective tissue: infrequently: muscle weakness, muscle cramps.
Disorders of the genitals and mammary gland: rarely: impotence.
General disorders and disorders at the injection site: often: fatigue ** infrequently: exhaustion **.
Laboratory and instrumental data: rarely: increased activity of hepatic transaminases in the blood (aspartate aminotransferase (ACT), alanine aminotransferase (ALT)).
** Especially often, these symptoms appear at the beginning of treatment. Typically, these phenomena are mild and go away, usually within 1-2 weeks after the start of treatment.
Drug interaction
Amlodipine:
The simultaneous use of amlodipine with thiazide diuretics, beta-adrenergic blocking agents, long-acting nitrates, sublingual nitroglycerin drugs, non-steroidal anti-inflammatory drugs, hypoglymic antibiotics is considered safe.
CYP3A4 Inhibitors: Amlodipine should be used with caution in conjunction with CYP3A4 inhibitors. Although adverse events related to such an interaction were not reported.
Inducers CYP3A4: Concomitant use with inducers of CYP3A4 (including rifampicin, St. John’s wort perforated) can lead to a decrease in the concentration of amlodipine in blood plasma. Amlodipine should be used with caution concurrently with CYP3A4 inducers. Grapefruit juice, cimetidine, aluminum / magnesium (as part of antacids) and sildenafil do not affect the pharmacokinetics of amlodipine.
Amlodipine may enhance the antihypertensive effect of other antihypertensive drugs.
Amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, ethanol (beverages containing alcohol), warfarin, or cyclosporine.
Amlodipine has no effect on laboratory parameters.
For bisoprolol:
Not recommended combinations
Slow calcium channel blockers (BMKCs) such as verapamil and, to a lesser extent, diltiazem, while using bisoprolol, can lead to a decrease in myocardial contractility, a marked decrease in blood pressure and impaired AV conduction. In particular, intravenous administration of verapamil to patients taking beta-blockers, may lead to severe arterial hypotension and AV block.
Centrally acting antihypertensive drugs (such as clonidine, methyldopa, moxonidine, rilmenidine) when used together with bisoprolol can lead to a reduction in heart rate and a decrease in cardiac output, as well as to vasodilation due to a decrease in central sympathetic tone. Abrupt withdrawal, especially before the abolition of beta-blockers, may increase the risk of developing “rebound” arterial hypertension.
Combinations requiring caution
BMKK derivatives of dihydropyridine (eg, nifedipine) when used concomitantly with bisoprolol may increase the risk of hypotension. In patients with heart failure, the risk of a subsequent deterioration in cardiac contractile function cannot be ruled out.
Class I antiarrhythmic drugs (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone) with simultaneous use with bisoprolol can reduce AV conductivity and myocardial contractility.
Class III antiarrhythmic drugs (e.g., amiodarone) may increase impairment of AV conduction.
Parasympathomimetics when used simultaneously with bisoprolol can increase the violation of AV conduction and increase the risk of developing bradycardia.
Topical beta-blockers (for example, eye drops for glaucoma) can enhance the systemic effects of bisoprolol (lowering blood pressure, lowering heart rate).
The hypoglycemic effect of insulin or hypoglycemic agents for oral administration may be enhanced. Signs of hypoglycemia – in particular tachycardia – may be masked. Such interactions are more likely when using non-selective beta-blockers.
General anesthesia medications can weaken reflex tachycardia and increase the risk of developing hypotension (see Special Instructions).
Cardiac glycosides, when used concomitantly with bisoprolol, can lead to an increase in the duration of the pulse and to the development of bradycardia.
Nonsteroidal anti-inflammatory drugs (NSAIDs) may decrease the antihypertensive effect of bisoprolol.
The simultaneous use of bisoprolol with beta-adrenergic agonists (for example, isoprenaline, dobutamine) can lead to a decrease in the effect of both drugs.
Combination of bisoprolol with adrenergic agonists affecting beta and alpha adrenoreceptors (e.g. norepinephrine, epinephrine) can enhance the vasoconstrictive effects of these drugs that occur with the participation of alpha-adrenergic receptors, leading to an increase in blood pressure. Such interactions are more likely when using non-selective beta-blockers.
Antihypertensive drugs, as well as other drugs with a possible antihypertensive effect (for example, tricyclic antidepressants, barbiturates, phenothiazines) can enhance the antihypertensive effect of bisoprolol.
Combinations that
needs to be considered Mefloquine while used with bisoprolol may increase the risk of developing bradycardia.
MAO inhibitors (with the exception of MAO B inhibitors) may enhance the antihypertensive effect of beta-blockers. Simultaneous use can also lead to the development of a hypertensive crisis.
Rifampicin shortens the half-life (T1 / 2) of bisoprolol slightly. As a rule, dose adjustment is not required.
Ergotamine derivatives when used concomitantly with bisoprolol increase the risk of peripheral circulation disturbance.
Overdose
For amlodipine:
Symptoms: marked decrease in blood pressure with possible development of reflex tachycardia and excessive peripheral vasodilation (risk of severe and persistent arterial hypotension, incl. with the development of shock and death).
Treatment: gastric lavage, appointment of activated charcoal, maintenance of cardiovascular function, control of cardiac and pulmonary function, elevated limb position, control of circulating blood volume and diuresis. Intensive symptomatic therapy. To restore the tone of the vessels – the use of vasoconstrictor drugs (in the absence of contraindications to their use) to eliminate the effects of calcium channel blockade – intravenous administration of calcium gluconate. Hemodialysis is not effective.
By bisoprolol
Symptoms: AV blockade, marked bradycardia, severe BP, bronchospasm, acute heart failure and hypoglycemia. The sensitivity to a single high dose of bisoprolol varies greatly between patients and, patients with CHF are likely to have high sensitivity.
Treatment: in the event of an overdose, first of all, it is necessary to discontinue the drug and start supportive symptomatic therapy.
In severe bradycardia: intravenous atropine. If the effect is insufficient, it is possible to enter with caution the positive chronotropic action with caution. Occasional staging of an artificial rhythm driver may be required.
With a marked decrease in blood pressure: intravenous administration of plasma replacement solutions and vasopressor drugs. Glucagon intravenous administration may also be indicated.
With AV blockade: patients should be monitored continuously and treated with beta-adrenomimetics such as epinephrine. If necessary – production of an artificial rhythm driver.
When exacerbation of the course of CHF: intravenous administration of diuretics, drugs with positive inotropic effect, as well as vasodilators.
In bronchospasm: the appointment of bronchodilators, including beta2-adrenomimetics and / or aminophylline.
In hypoglycemia: intravenous dextrose (glucose).
Bisoprolol practically cannot be dialyzed.
Storage conditions
Do not store above 30 ° C.
Keep this medicine out of the reach of children!
Shelf life
3 years.
Deystvuyushtee substance
Amlodipine, Bisoprolol
drugstore conditions
drugstore
dosage form
tablets
Possible product names
CONCOR AM 0.005 + 0.005 N30 TABLE
Concor AM 5mg + 5mg Tab. X30
CONCOR AM 5MG. + 5MG. No. 30 TAB.
Concor AM tab 5mg + 5mg N30
Concor AM tab. 5 mg + 5 mg No. 30
Merck KGaA, Russia
