Expiration date: 10/2025
International nonproprietary name (INN): bisoprolol+amlodipine
Dosage form: tablets
Composition: 1 tablet product contains:
Active substance:
5 mg bisoprolol fumarate and 5 mg amlodipine (in the form of 6.95 mg of amlodipine besylate)
5 mg bisoprolol fumarate and 10 mg amlodipine (in the form of a 13.9 mg of amlodipine besylate)
10 mg bisoprolol fumarate and 5 mg amlodipine (in the form of 6.95 mg of amlodipine besylate)
10 mg bisoprolol and 10 mg of amlodipine (in the form of a 13.9 mg of amlodipine besylate) fumarate
Excipients:
cellulose microcrystalline 130,55/261,1/263,05/261,1 mg, carboximetilkrahmal sodium (type a) 5/10/10/10 mg, magnesium stearate 1,5/3,0/3,0/3,0 mg, silica colloidal anhydrous 1/2/2/2 mg.
Description:
Tablets 5 mg+5 mg: white or almost white oblong, slightly biconvex tablets, scored on one side and engraved with MS on the other side of the tablet, odorless.
Tablets 5 mg+10 mg: white or almost white round flat tablets with beveled edges, scored on one side tablets engraved with MS on the other side of the tablet, odorless.
Tablets 10 mg+5 mg: white or almost white, oval, slightly biconvex tablets, scored on one side tablets engraved with MS on the other side of the tablet, odorless.
Tablets 10 mg+10 mg: white or almost white, round, slightly biconvex tablets, scored on one side and engraved with MS on the other side of the tablet, odorless.
Pharmacotherapeutic group: antihypertensive combo (beta1-selective blocker + blocker of "slow" calcium channels (bmkk))
Pharmacological action
Pharmacodynamics
This drug has a pronounced antihypertensive and antianginal effects, due to complementary action of two active ingredients: bmkk – amlodipine and selective beta1-blocker is bisoprolol.
The mechanism of action of amlodipine:
Amlodipine blocks calcium channels, lowers transmembranny transition of calcium ions into the cell (more in gladkomyshechne cells receptacles, than cardiomiotita).
The antihypertensive effect of amlodipine is due to a direct relaxing effect on vascular smooth muscle cells, which leads to a decrease in peripheral vascular resistance.
Mechanism of antianginal action not fully understood, maybe he is linked to two following effects:
The peripheral arterioles, reduces the total peripheral resistance, ie afterload. Because amlodipine does not cause reflex tachycardia, consumption of energy and oxygen by the myocardium is reduced.
Expansion of large coronary arteries and coronary arterioles improves oxygen supply to both normal and ischemic areas of the myocardium. Due to these effects improves the oxygen supply of the myocardium, even when spasm of the coronary arteries (Prinzmetal's angina or unstable angina).
In patients with hypertension receiving the drug once a day causes clinically significant decrease AD in the lying position and standing throughout the 24-hour interval between meals preparation. Due to the slow development of the antihypertensive effect of amlodipine it does not cause acute hypertension hypotension.
In patients with angina pectoris taking the drug once a day increases the total time of the exercise, the time to development of angina, and time to significant reduction in the interval ST, and reduces the frequency of angina attacks and the need for sublingual intake of nitroglycerin.
Not detected negative effects of amlodipine on the lipid metabolism of blood plasma, blood glucose and uric acid in the blood serum.
The mechanism of action of bisoprolol:
Bisoprolol is a selective beta1-blocker without own sympathomimetic activity, has membrane stabilizing effect.
It has only a slight affinity for beta2-adrenergic receptors of smooth muscles of bronchi and vessels, as well as to the beta2-adrenergic receptors involved in the regulation of metabolism. Therefore, bisoprolol does not affect the airway resistance and the metabolic processes with the involvement of beta2-adrenergic receptors.
Selective drug action on the beta1-adrenergic receptors remains outside the therapeutic range.
Bisoprolol has no pronounced negative inotropic effects. The maximum effect of the drug is achieved in 3-4 hours after ingestion. Even in the appointment of bisoprolol 1 per day its therapeutic effect persists for 24 hours thanks to the 10-12 hour half-life period from blood plasma. As a rule, the maximum antihypertensive effect is attained within 2 weeks after the start of treatment.
Bisoprolol reduces the activity of the sympathoadrenal system (SAS), blocking beta1-adrenergic receptors of the heart.
After a single oral administration in patients with coronary artery disease (CAD) without signs of chronic heart failure (CHF) bisoprolol slows the heart rate (heart rate), reduces stroke volume of the heart and, consequently, reduces the ejection fraction and the need heart of oxygen. With long-term therapy initially increased total peripheral vascular resistance (SVR) decreases. The reduction in renin activity in blood plasma is considered as one of the components of the hypotensive effect of beta-blockers.
Pharmacokinetics
Amlodipine:
Suction:
Amlodipine is well absorbed after oral administration. The maximum concentration in plasma observed after 6-12 h. taking the drug with food does not affect its absorption. The absolute bioavailability is 64% to 80%.
Distribution:
The apparent volume of distribution is 21 l/kg. Equilibrium concentration in plasma (5-15 ng/ml) is achieved after 7-8 days after the start of treatment. In vitro studies have shown that circulating amlodipine is approximately 93-98% is associated with blood plasma proteins.
Metabolism and excretion:
Amlodipine undergoes extensive metabolism in the liver. Approximately 90 % of the dose is converted to inactive pyridine derivatives. Approximately 10 % of the dose is excreted in the urine unchanged. Approximately 60% of inactive metabolites excreted by the kidneys and 20-25% through the intestines. The decrease in the concentration in blood plasma is biphasic. The final elimination half-life is about 35-50 hours, which allows to inject the drug once a day. Total clearance is 7 ml/min/kg (25 l/HR in a patient weighing 60 kg). In elderly patients it is 19 l/h.
Elderly patients and patients with renal insufficiency was not observed significant changes in the pharmacokinetics of amlodipine.
Due to the decrease in clearance in patients with hepatic insufficiency should be assigned a lower initial dose.
Bisoprolol:
Suction. Bisoprolol is almost completely (90%) absorbed from the gastrointestinal tract. Its bioavailability due to low metabolism "first pass" through the liver (approximately 10%) is about 90% after oral administration. Food intake does not affect bioavailability. Bisoprolol exhibits linear kinetics, and its concentration in blood plasma is proportional to the dose in the range of 5 to 20 mg. the Maximum concentration in plasma achieved in 2-3 hours.
Distribution. Bisoprolol is distributed quite widely. The distribution volume is 3.5 l/kg. the Relationship with blood plasma proteins is about 30%.
Metabolism. Metabolized via the oxidative pathway without subsequent conjugation. All metabolites are polar (water soluble) and excreted by the kidneys. The main metabolites detected in plasma and urine, does not exhibit a pharmacological activity. The data obtained in the result of experiments with human liver microsomes in vitro indicate that bisoprolol is metabolized primarily via CYP3A4 (about 95%), and the isoenzyme CYP2D6 plays only a minor role.
Excretion. The clearance of bisoprolol is determined by a balance between renal excretion in unchanged form (about 50%) and hepatic metabolism (about 50%) to metabolites which are also excreted by the kidneys. Total clearance is 15 l/h. The half-life is 10-12 hours.
Indications for use
Hypertension: replacement therapy mono-component drugs, amlodipine and bisoprolol at the same doses.
Contraindications
For amlodipine:
unstable angina (with the exception of strokes Prinzmetala),
acute myocardial infarction (within the first 28 days)
clinically significant aortic stenosis.
Bisoprololu:
acute heart failure or chronic heart failure (CHF) decompensation requiring inotropic therapy
atrioventricular (AV) blockade II and III degree, without a pacemaker,
syndrome sick sinus (SSSU),
sinoatrial block,
bradycardia (heart rate less than 60 beats/min ),
severe forms of bronchial asthma or chronic obstructive pulmonary disease (COPD),
expressed human peripheral blood circulation or Raynaud's syndrome,
pheochromocytoma (without the simultaneous use of alpha-blockers),
metabolic acidosis,
The combination of amlodipine/bisoprolol:
hypersensitivity to amlodipine, other derivatives of dihydropyridine, bisoprololu and/or any of the excipients,
severe hypotension (systolic BP less than 100 mm Hg.St.),
shock (including cardiogenic),
children up to age 18 years (effectiveness and safety have not been established)
With caution
CHF (incl. non-ischemic etiology III-IV functional class NYHA classification), hepatic failure, renal failure, hyperthyroidism, diabetes mellitus, with considerable fluctuations of concentration of glucose in the blood, AV blockade of I degree, Prinzmetal's angina, occlusive peripheral arterial disease, psoriasis (including in history), fasting (strict diet), pheochromocytoma (with simultaneous use of alpha-blockers), bronchial asthma and COPD, held simultaneously desensitizing therapy, General anaesthesia, advanced age, hypotension, diabetes type 1, aortic stenosis, mitral stenosis, acute myocardial infarction (after the first 28 days).
Application of pregnancy and breastfeeding (lactation)
For amlodipine:
In experimental studies fetotoksicheskoe and embryotoxic effect of the drug is not established, but use during pregnancy only when benefit to the mother outweighs the potential risk to the fetus.
No evidence of excretion of amlodipine with breast milk. However, it is known that other bmkk – dihydropyridine derivatives, are excreted in breast milk. In this connection, the appointment of amlodipine during lactation should decide the issue of termination of breastfeeding.
Bisoprololu:
The use of bisoprolol during pregnancy is possible only in the case when the expected benefit to the mother outweighs the potential risk to the fetus. Beta-blockers reduce blood flow to the placenta and can affect fetal development. You should monitor the blood flow in the placenta and uterus, as well as to observe the growth and development of the unborn child, and in case of occurrence of adverse events in relation to pregnancy and/or foetus, alternative methods of therapy.
You should carefully examine the newborn after birth. In the first three days of life can cause symptoms of bradycardia and hypoglycemia. Data on the allocation of bisoprolol in the breast milk is not. Therefore, it is not recommended for women during lactation. If the receiving bisoprolol during lactation is necessary, breastfeeding should be discontinued.
Method of application and doses
Tablets for oral administration. The tablets should be taken in the morning, regardless of the meal, not liquid.
The recommended daily dose - 1 tablet per day specific dosage.
Selection and titration doses for each patient individually by the doctor during the appointment monocomponent drugs containing the active ingredients in the drug Concor® AM.
The duration of treatment
Treatment with Concor® AM is usually long-term therapy.
The liver
In patients with impaired liver function the excretion of amlodipine may be slowed. Special dosage regimen for this group of patients is not defined, however, the drug must be administered with caution.
For patients with severely impaired hepatic function the maximum daily dose of bisoprolol is 10mg.
Violation of kidney function
Patients with impaired renal function mild or moderate severity of dosage adjustment usually not required. Amlodipine is not displayed by dialysis. Patients undergoing dialysis should prescribe amlodipine with caution.
For patients with severe renal impairment (creatinine clearance (CC) less than 20 ml/min) the maximum daily dose of bisoprolol is 10mg.
Elderly patients
Older patients may be administered usual doses of the drug. Caution is required only when increasing the dose.
Children
The drug is not recommended for use in children under the age of 18 in the absence of data on efficacy and safety.
Treatment should not be discontinued abruptly, as this can lead to a temporary deterioration of the clinical condition. Especially treatment should not be abruptly discontinue in patients with coronary artery disease. It recommended a gradual dose reduction.
Side effects
The adverse reactions observed when using the active ingredients separately submitted in accordance with the following criteria groups according to frequency:
Very frequent >,,1/10, common >,,1/100 - <,,1 10="" span="" style="text-decoration: underline," data-mce-style="text-decoration: underline,">,,>,,1/1 000 - <,,1 100="" span="" style="text-decoration: underline," data-mce-style="text-decoration: underline,">,,>,,1/10 000 - <,,1 1="" 000="" 10="" br="">,,amlodipine: disorders of the blood and lymphatic system: very rare: leukopenia, thrombocytopenia.
Violations by the immune system: very rare: allergic reaction.
Violations of metabolism and nutrition: very rare: hyperglycemia.
Psychiatric disorders: uncommon: insomnia, mood changes (including anxiety), depression rare: confusion.
Violations of the nervous system: common: headache, dizziness, sleepiness (especially at the beginning of the treatment) uncommon: syncope, hypoesthesia, paresthesia, dysgeusia, tremor very rare: muscular hypertension, peripheral neuropathy.
Violations of the organ of vision: infrequent: visual impairment (including diplopia).
Violations of the organ of hearing and labyrinth disorders: uncommon: tinnitus.
Violations by the gastrointestinal tract: common: nausea, abdominal pain uncommon: vomiting, changes in bowel movements (i.e. constipation or diarrhea), dyspepsia, dry mucous membranes of the mouth, very rarely - gastritis, gingival hyperplasia, pancreatitis.
Violations of the liver and biliary tract: very rare: hepatitis*, jaundice*.
Disorders of the heart: frequent: palpitations very rare: myocardial infarction, arrhythmia (bradycardia, ventricular tachycardia, atrial fibrillation).
Violations by vessels: often: "tides" of blood to the face, not often: expressed lower AD, very rare: vasculitis.
Violations of the respiratory system, chest and mediastinum disorders: uncommon: dyspnoea, rhinitis very rare: cough.
Violations of the kidney and urinary tract disorders: uncommon: pollakiuria, painful urge to urinate, nocturia.
Violations of the genital organs and mammary gland: uncommon: impotence, gynecomastia.
General disorders injection site: frequent: peripheral edema, fatigue, uncommon: chest pain, asthenia, pain, malaise.
Violations by musculoskeletal and connective tissue: frequent: oedema of ankles, uncommon: arthralgia, myalgia, muscle cramps, back pain.
Violations from skin and hypodermic skin: uncommon: alopecia, purpura, skin discoloration, increased sweating, pruritus, rash, exanthema very rare: angioneurotic edema, exudative erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, angioedema, photosensitivity.
Laboratory and instrumental data: uncommon: weight gain, weight loss very rare: increased activity of "liver" enzymes*.
* In most cases with cholestasis
Bisoprololu:
Violations of metabolism and nutrition: rare: increased concentration of triglycerides.
Psychiatric disorders: uncommon: depression rare: hallucinations, nightmares.
Violations of the nervous system: common: headache** dizziness**, uncommon: insomnia, rare: syncope.
Violations of the organ of vision: rare: reduced lacrimation (to consider when wearing contact lenses) very rare: conjunctivitis.
Violations of the organ of hearing and labyrinth disorders: rare: hearing disorders.
Disorders of the heart: rare: impaired AV conduction, bradycardia, aggravation of current symptoms of CHF.
Violations by vessels: frequent: sensation of cold or numbness in the limbs, marked reduction in blood pressure, uncommon: orthostatic hypotension.
Violations of the respiratory system, chest and mediastinum disorders: uncommon: bronchospasm in patients with bronchial asthma or airway obstruction, a history of rare: allergic rhinitis.
Violations by the gastrointestinal tract: common: nausea, vomiting, diarrhea, constipation.
Violations of the liver and biliary tract disorders: rare: hepatitis.
Violations from skin and hypodermic skin: rare: hypersensitivity reactions such as itching, rash, hyperemia of skin, very rare: alopecia. Beta-blockers can exacerbate symptoms of psoriasis or induce psoriasiform rash.
Violations by musculoskeletal and connective tissue: uncommon: muscle weakness, muscle cramps.
Violations of the genital organs and breast cancer: rare: impotence.
General disorders injection site: frequent: fatigue**, uncommon: exhaustion**.
Laboratory and instrumental data: rarely: increased activity of "liver" transaminases in the blood (aspartate aminotransferase (ACT), alanine aminotransferase (ALT)).
** Especially often these symptoms appear early in the course of treatment. Usually these effects are mild nature and are usually within 1-2 weeks after starting treatment.
Overdose
For amlodipine:
Symptoms: expressed lower AD with the possible development of reflex tachycardia and excessive peripheral vasodilatation (risk of severe and persistent arterial hypotension, including shock and death).
Treatment: gastric lavage, the appointment activated carbon, the maintenance functions of the cardiovascular system, monitoring of indicators of function of heart and lungs, exalted position of extremities, control of blood volume and urine output. Intensive symptomatic therapy. To restore vascular tone - the use of vasoconstrictor drugs (with no contraindications to their use), to eliminate the effects of the blockade of calcium channels - intravenous calcium gluconate. Hemodialysis is not effective.
Bisoprololu
Symptoms: AV blockade, bradycardia, marked reduction in blood pressure, bronchospasm, acute cardiac insufficiency and hypoglycaemia. Sensitivity to receive a single high dose of bisoprolol is highly variable among individual patients and probably patients with CHF have a high sensitivity.
Treatment: in the event of an overdose, especially, need to stop taking the drug and initiate supportive symptomatic treatment.
In severe bradycardia: intravenous administration of atropine. If the effect is insufficient, with care it is possible to introduce a means of having a positive chronotropic effect. Sometimes you may need a temporary production of an artificial pacemaker.
In marked decrease in blood pressure: intravenous administration of plasma-substituting solutions and vasopressor drugs. Can also be shown intravenous glucagon.
AV blockade: patients should be under constant observation, and to treatment beta-agonists such as epinephrine. In case of need - the production of an artificial pacemaker.
When exacerbation of CHF: intravenous diuretics, drugs with positive inotropic effect, as well as vasodilators.
If bronchospasm: appointment of bronchodilators, including beta2-agonists and/or aminophylline.
Hypoglycemia: intravenous dextrose (glucose).
Bisoprolol is virtually impossible to dialysis.
Interaction with other drugs
For amlodipine:
The simultaneous use of amlodipine with thiazide diuretics, beta-blockers, nitrates, long-acting, sublingually drugs nitroglycerin, nonsteroidal anti-inflammatory drugs, antibiotics and hypoglycemic agents for oral administration is considered safe.
CYP3A4 inhibitors: Should be used with caution amlodipine concurrently with CYP3A4 inhibitors. Although adverse events attributable to such interaction have not been reported.
Inducers of CYP3A4: concomitant use with CYP3A4 inducers (i.e. rifampicin, Hypericum perforatum) may lead to a decrease in the concentration of amlodipine in plasma. Should be used with caution amlodipine concurrently with CYP3A4 inducers. Grapefruit juice, cimetidine, aluminium/magnesium (the antacid) and sildenafil did not affect the pharmacokinetics of amlodipine.
Amlodipine may enhance the antihypertensive effect of other antihypertensive agents.
Amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, ethanol (beverages containing alcohol), warfarin or cyclosporine.
Amlodipine has no effect on laboratory parameters.
Bisoprololu:
Not recommended combinations
Blockers "slow" calcium channels (bmkk) of the verapamil type and to a lesser extent, diltiazem, while the use of bisoprololum can lead to a decrease in myocardial contractility, a pronounced reduction in blood pressure and impaired AV conduction. In particular, intravenous administration of verapamil to patients receiving beta-blockers may lead to severe hypotension and AV blockade.
Antihypertensive drugs of Central action (such as clonidine, methyldopa, moxonidine, rilmenidine) while the use of bisoprololum can lead to slowing the heart rate and decrease cardiac output and 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" hypertension.
Combinations requiring caution
Bmkk derivatives of dihydropyridine (e.g., nifedipine) together with the use of bisoprololum can increase the risk of hypotension. In patients with CHF, we cannot exclude the risk of subsequent deterioration of the contractile function of the heart.
Antiarrhythmic agents of class I (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainid, propafenon) while the use of bisoprololum can reduce AV conduction and myocardial contractility.
Antiarrhythmic agents of class III (e.g. amiodarone) may increase the violation of AV conduction.
Parasympathomimetic while the use of bisoprolol may increase the violation of AV conduction and increase the risk of bradycardia.
Effect of beta-blockers for topical application (e.g. eye drops for glaucoma treatment) may exacerbate the systemic effects of bisoprolol (decrease in blood pressure, slowing the heart rate).
The hypoglycemic action of insulin or hypoglycemic agents for oral administration can be enhanced. The signs of hypoglycemia, particularly tachycardia, may be masked. Such interaction is more likely with use of nonselective beta-blockers.
Funds for General anesthesia can attenuate reflex tachycardia and increase the risk of hypotension (see section "Special instructions").
Cardiac glycosides while the use of bisoprololum can lead to an increase in time of the pulse and to the development of bradycardia.
Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the antihypertensive effect of bisoprolol.
The simultaneous use of bisoprolol with beta-agonists (e.g., isoprenaline, dobutamine) may cause decreased effect of both drugs.
Combination of bisoprolol with agonists affecting beta - and alpha-adrenoceptors (e.g. norepinephrine, epinephrine) can potentiate the vasoconstrictor effects of these means that occur with the participation of alpha-adrenergic receptors, leading to increased blood pressure. Such interaction is more likely with use of nonselective beta-blockers.
Antihypertensives, as well as other means with possible antihypertensive effects (eg, tricyclic antidepressants, barbiturates, phenothiazines) may increase the antihypertensive effect of bisoprolol.
Combinations to be taken into account
Mefloquine while the use of bisoprololum can increase the risk of bradycardia.
MAO inhibitors (except MAO inhibitors) may enhance the antihypertensive effect of beta-blockers. The simultaneous use can also lead to the development hypertensive crisis.
A bit of rifampicin shortens the half-life (T1/2) of bisoprolol. Generally, dose adjustment is not required.
Ergotamine derivatives while the use of bisoprololum increase the risk of developing peripheral circulatory disorders.
Special instructions (see also section "C care")
For amlodipine:
Patients with heart failure should take amlodipine with caution. In patients with cardiac insufficiency stage III-IV NYHA classification amlodipine increases the risk of pulmonary edema that is not associated with the worsening of CHF symptoms current.
Bisoprololu:
Discontinuation of treatment with bisoprolol should not be sudden, particularly in patients with CHD, unless there are clear indications for the removal of the drug. Sudden withdrawal of bisoprolol may lead to a temporary deterioration of cardiac pathology.
Bisoprolol should be administered with extreme caution to patients with hypertension or angina, combined with heart failure.
As with other beta-blockers, bisoprolol may increase sensitivity to allergens and increased anaphylactic reactions, so care must be taken when simultaneously carried out desensitizing therapy. The use of adrenaline may not always give the expected therapeutic effect.
When you use bisoprolol, symptoms of hyperthyroidism may be masked.
In patients with pheochromocytoma bisoprolol should be administered only after the blockade of alpha-adrenergic receptors.
Before General anaesthesia, the anaesthetist should be informed that the patient is taking beta-blockers. If you want to reverse beta-blocker before surgery, this should be done gradually and completed about 48 hours before anaesthesia.
In bronchial asthma or COPD showed the simultaneous application of bronchodilatory funds. In patients with bronchial asthma may increase the airway resistance, which requires higher doses of beta2-agonists.
Effects on ability to drive vehicles and mechanisms
During the period of treatment it is necessary to exercise caution in driving and working with technically complex mechanisms.
Release form
Tablets 5 mg + 5 mg, 5 mg + 10 mg, 10 mg + 5 mg, 10 mg + 10 mg.
10 tablets in blisters of a composite film "??ld" (polyamide/aluminium foil/PVC)// aluminum foil. 3 blisters of 10 tablets Packed in a cardboard box together with instruction manual.
Shelf life
3 years.
Do not use after the expiry date shown on the packaging.
Storage conditions
Keep at temperature not exceeding 30°C.
Keep out of reach of children!
