Concor Combi

Concor Combi

Amlodipine, Bisoprolol

Arterial hypertension: replacement of therapy with monocomponent drugs amlodipine and bisoprolol in the same doses.

Inside, in the morning, regardless of the meal, without chewing. The riska is only intended to facilitate breaking for ease of swallowing. Not to divide into equal doses!

The recommended daily dose is 1 tablet. a certain dosage per day.

The selection and titration of the dose individually for each patient is carried out by the doctor during the appointment of monocomponent drugs containing the active ingredients that are part of the Concor drug^® AM.

Duration of treatment

Treatment with Concor^® AM is usually a long-term therapy. Treatment should not be stopped abruptly, as this may lead to a temporary deterioration of the clinical condition. Especially treatment should not be abruptly discontinued in patients with CHD. A gradual dose reduction is recommended.

Impaired liver function. In patients with impaired liver function, the elimination of amlodipine may be slowed. 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 severe hepatic impairment, the maximum daily dose of bisoprolol is 10 mg.

Impaired renal function. Patients with mild or moderate renal impairment usually do not need to adjust the dosage regimen. Amlodipine is not eliminated by dialysis. Patients undergoing dialysis should be prescribed amlodipine with extreme caution.

For patients with severe renal impairment (creatinine Cl less than 20 ml/min), the maximum daily dose of bisoprolol is 10 mg.

Elderly patients. Elderly patients may be prescribed regular doses of the drug. Caution is only required when increasing the dose.

Children. The drug is not recommended for use in children under the age of 18 years due to the lack of data on efficacy and safety.

Amlodipine

severe arterial hypotension,

shock (including cardiogenic shock),

unstable angina (with the exception of Prinzmetal angina),

hemodynamically unstable heart failure after acute myocardial infarction,

left ventricular outlet obstruction (e.g. clinically significant aortic stenosis).

Bisoprolol

acute heart failure or chronic heart failure (CHF) in the decompensation stage, requiring inotropic therapy,

cardiogenic shock,

AV block of II and III degree, without pacemaker,

sinus node weakness syndrome (SSS),

sinoatrial blockade,

severe bradycardia (heart rate less than 60 beats / min),

symptomatic arterial hypotension,

severe forms of bronchial asthma,

severe peripheral arterial circulation disorders or Raynaud's syndrome,

pheochromocytoma (without simultaneous use of alpha-blockers),

metabolic acidosis,

The combination of amlodipine/bisoprolol

hypersensitivity to amlodipine, other dihydropyridine derivatives, bisoprolol, and / or any of the excipients,

children under 18 years of age (efficacy and safety have not been established).

With caution: chronic heart failure (including non-ischemic etiology of the III–IV functional class according to the classification NYHA), hepatic insufficiency, renal insufficiency, hyperthyroidism, type 1 diabetes mellitus, diabetes mellitus with significant fluctuations in blood glucose concentration, strict diet, simultaneous desensitizing therapy, grade I AV block, Prinzmetal angina pectoris, mild to moderate peripheral arterial circulation disorder, psoriasis (in t.tsch. in anamnesis), pheochromocytoma (with simultaneous use of alpha-blockers), severe forms of chronic obstructive pulmonary disease and non-severe forms of bronchial asthma, general anesthesia, elderly age, hypotension, aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, acute myocardial infarction (during the first month), simultaneous use with inhibitors or inducers of the CYP3A4 isoenzyme

Adverse reactions observed when using active substances separately are presented below, depending on the frequency of their occurrence: very often ≥1/10, often ≥1/100 and <1/10, infrequently ≥1/1000 and <1/100, rarely ≥1/10000 and <1/1000, very rarely <1/10000, including individual cases, the frequency is unknown (it is impossible to estimate based on available data).

Amlodipine

From the blood and lymphatic system: very rarely — leukopenia, thrombocytopenia.

On the part of the immune system: very rarely — allergic reactions.

From the side of metabolism and nutrition: very rarely — hyperglycemia.

Mental disorders: infrequently-insomnia, mood changes (including anxiety), depression, rarely-confusion.

From the nervous system: often-drowsiness, dizziness, headache (especially at the beginning of treatment), infrequently-fainting, hypesthesia, paresthesia, dysgeusia, tremor, very rarely-muscle hypertension, peripheral neuropathy.

On the part of the visual organ: often-visual impairment (including diplopia).

On the part of the organ of hearing and labyrinth disorders: infrequently-tinnitus.

From the gastrointestinal tract: often-nausea, abdominal pain, dyspepsia, changes in the mode of defecation (including constipation or diarrhea), infrequently-vomiting, dryness of the oral mucosa, very rarely-gastritis, gum hyperplasia, pancreatitis.

From the liver and biliary tract: very rarely-hepatitis, jaundice, increased liver enzymes*.

From the heart: often-a feeling of palpitation, infrequently-arrhythmia (bradycardia, ventricular tachycardia, atrial fibrillation), very rarely-myocardial infarction.

From the side of the vessels: often-hot flashes, infrequently-a marked decrease in blood pressure, very rarely-vasculitis.

From the respiratory system, chest and mediastinal organs: often-shortness of breath, infrequently-cough, rhinitis.

From the kidneys and urinary tract: infrequently-pollakiuria, urination disorder, nocturia.

From the genitals and breast: infrequently-impotence, gynecomastia.

General disorders and disorders at the injection site: very often — peripheral edema, often-increased fatigue, asthenia, infrequently-chest pain, pain, general malaise.

From the musculoskeletal system and connective tissue: often-swelling of the ankles, muscle cramps, infrequently-arthralgia, myalgia, back pain.

From the skin and subcutaneous tissues: infrequently — alopecia, purpura, skin discoloration, increased sweating, itching, rash, exanthema, urticaria, very rarely-angioedema, exudative erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity.

Laboratory and instrumental data: infrequently — an increase in body mass, reduction of body weight.

Isolated cases of extrapyramidal syndrome have been reported.

Bisoprolol

From the side of metabolism and nutrition: rarely-an increase in the concentration of triglycerides.

Mental disorders: infrequently-depression, sleep disorders, rarely-hallucinations, nightmares.

From the nervous system: often-headache**, dizziness**, infrequently-insomnia, rarely-fainting.

On the part of the visual organ: rarely-reduced lacrimation (should be taken into account when wearing contact lenses), very rarely-conjunctivitis.

On the part of the organ of hearing and labyrinth disorders: rarely-hearing disorders.

From the heart: infrequently-violation of AV-conduction, bradycardia, aggravation of symptoms of CHF.

From the side of the vessels: often-a feeling of coldness or numbness in the extremities, infrequently-hypotension.

From the respiratory system, chest and mediastinal organs: infrequently-bronchospasm in patients with a history of bronchial asthma or obstructive pulmonary disease, rarely-allergic rhinitis.

From the gastrointestinal tract: often — nausea, vomiting, diarrhea, constipation.

From the liver and biliary tract: rarely-hepatitis.

From the skin and subcutaneous tissue: rarely-hypersensitivity reactions, such as itching, rash, hyperemia of the skin, very rarely-alopecia, beta-blockers can exacerbate the symptoms of psoriasis or cause a psoriasis-like rash.

From the musculoskeletal system and connective tissue: infrequently-muscle weakness, muscle cramps.

From the genitals and breast: rarely-impotence.

General disorders and disorders at the injection site: often-increased fatigue**, infrequently-exhaustion**.

Laboratory and instrumental data: rarely-increased activity of hepatic transaminases in the blood ACT, ALT.

*In most cases with cholestasis.

** These symptoms appear especially often at the beginning of the course of treatment. Usually these phenomena are mild and usually pass within 1-2 weeks after the start of treatment.

Amlodipine

Symptoms: a marked decrease in blood pressure with the possible development of reflex tachycardia and excessive peripheral vasodilation (the risk of developing severe and persistent arterial hypotension, including with the development of shock and death).

Treatment: gastric lavage, administration of activated charcoal, maintenance of CCC function, monitoring of heart and lung function, elevation of the lower extremities, control of BCC and diuresis. Intensive symptomatic therapy. To restore vascular tone — the use of vasoconstrictive drugs (in the absence of contraindications to their use), to eliminate the effects of calcium channel blockade-intravenous administration of calcium gluconate. Hemodialysis is ineffective.

Bisoprolol

Symptoms: The most common symptoms of overdose are AV block, severe bradycardia, marked decrease in blood pressure, bronchospasm, acute heart failure, and hypoglycemia. Sensitivity to a single dose of high-dose bisoprolol varies greatly among individual patients, and it is likely that patients with CHF have a high sensitivity.

Treatment:

If an overdose occurs, first of all, it is necessary to stop taking the drug and start supportive symptomatic therapy.

With severe bradycardia: intravenous administration of atropine. If the effect is insufficient, with caution, you can enter a tool that has a positive chronotropic effect. Sometimes you may need to temporarily install a pacemaker.

With a pronounced decrease in blood pressure: intravenous administration of plasma-substituting solutions and vasopressors. It may also be indicated in / in the administration of glucagon.

With AV block (II or III degree)): patients should be constantly monitored and treated with beta-adrenomimetics, such as epinephrine, isoprenaline infusions. If necessary, install a pacemaker.

With exacerbation of the course of CHF: intravenous administration of diuretics, drugs with a positive inotropic effect, as well as vasodilators.

With bronchospasm: appointment of bronchodilators, including beta₂- adrenomimetics and / or aminophylline.

With hypoglycemia: intravenous administration of dextrose (glucose).

Bisoprolol practically does not respond to dialysis.

This drug has pronounced antihypertensive and antianginal effects due to the complementary action of two active ingredients: BCC-amlodipine and selective beta₁- an adrenoblocker-bisoprolol.

Amlodipine

The mechanism of action. Amlodipine blocks calcium channels, reduces the transmembrane transfer of calcium ions into the cell (to a greater extent in vascular smooth muscle cells than in cardiomyocytes).

The antihypertensive effect of amlodipine is due to the direct relaxing effect on vascular smooth muscle cells, which leads to a decrease in the resistance of peripheral vessels.

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, i.e. post-loading. Since amlodipine does not cause reflex tachycardia, the energy and oxygen consumption of the myocardium is reduced.

2. The expansion of large coronary arteries and coronary arterioles improves the oxygen supply to both normal and ischemic areas of the myocardium. Thanks to these effects, the oxygen supply to the myocardium is improved even with coronary artery spasm (Prinzmetal angina or unstable angina).

In patients with arterial hypertension, taking the drug once a day causes a clinically significant decrease in blood pressure in the lying and standing position throughout the 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, the drug once a day increases the total execution time for exercise, time to development of angina, and time to a significant reduction in the interval ST1 mm and reduces the frequency of angina attacks and the need of receiving sublingual nitroglycerin.

Amlodipine is not associated with any adverse metabolic disorders or changes in plasma lipid levels. It can be used in patients with asthma, diabetes and gout.

Bisoprolol

The mechanism of action. Bisoprolol is a selective beta₁- the adrenoblocker, without its own sympathomimetic activity, does not have a membrane-stabilizing effect.

It has only a slight affinity for beta₂- adrenoreceptors of the smooth muscles of the bronchi and blood vessels, as well as to beta₂- adrenoreceptors involved in the regulation of metabolism. Therefore, bisoprolol in general does not affect the resistance of the respiratory tract and the metabolic processes in which beta-beta is involved.₂-adrenergic receptors.

Selective effect of the drug on beta₁adrenergic receptors and stored outside the therapeutic range.

Bisoprolol does not have a pronounced negative inotropic effect.

The maximum effect of the drug is achieved in 3-4 hours after oral administration.

Even when bisoprolol is prescribed once a day, its therapeutic effect persists for 24 hours due to a 10-12-hour T_1/2 from the 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 by blocking beta₁- adrenoreceptors of the heart.

With a single oral administration in patients with CHD without signs of CHF, bisoprolol reduces the heart rate, reduces the stroke volume of the heart and, as a result, reduces the ejection fraction and the need for oxygen in the myocardium. With long-term therapy initially elevated peripheral vascular resistance is reduced. A decrease in the activity of renin in the blood plasma is considered as one of the components of the hypotensive effect of beta-blockers.

Amlodipine

Suction. Amlodipine is well absorbed after oral administration. C_max in the blood plasma, it is noted after 6-12 hours. Taking the drug with food does not affect its absorption.

Absolute bioavailability is 64-80%. T_max amlodipine in plasma is similar in elderly and young patients.

Distribution. Visible V_d it is 21 l / kg. C_ss in the blood plasma (5-15 ng / ml) is reached in 7-8 days after the start of the drug. Researches in vitro The circulating amlodipine was shown to be approximately 97.5% bound to plasma proteins.

Metabolism and excretion. Amlodipine undergoes intensive metabolism in the liver. Approximately 90% of the dose is converted to inactive pyridine derivatives. Approximately 10% of the dose is excreted unchanged in the urine. Approximately 60% of the amount of inactive metabolites is excreted by the kidneys and 20-25% through the intestine. The decrease in the concentration in the blood plasma has a two-phase character. Final T_1/2 it is approximately 35-50 hours, which allows you to administer the drug once a 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.

The clearance of amlodipine tends to decrease with a subsequent increase in AUC and T_1/2 in elderly patients. Increase in AUC and T_1/2 in patients with congestive heart failure, it is expected for this studied age group of patients.

In patients with renal insufficiency, no significant changes in the pharmacokinetics of amlodipine were observed. Amlodipine is not dialyzed.

In patients with hepatic insufficiency due to a decrease in clearance, leading to a longer T_1/2 and an increase in AUC of approximately 40-60%, lower initial doses should be prescribed.

Bisoprolol

Suction. Bisoprolol is almost completely (more than 90%) absorbed from the gastrointestinal tract. Its bioavailability due to insignificant metabolism at the first pass through the liver (at a level of about 10%) is about 90% after oral administration. Food intake 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. C_max in the blood plasma, it is reached after 2-3 hours.

Distribution. Bisoprolol is distributed quite widely. V_d it is 3.5 l/kg. The binding to plasma proteins reaches about 30%.

Metabolism and excretion. It is metabolized by the oxidative pathway without subsequent conjugation. All metabolites are polar (water-soluble) and are excreted by the kidneys. The main metabolites found in blood plasma and urine do not exhibit pharmacological activity. Data obtained from experiments with human liver microsomes in vitro, show that bisoprolol is primarily metabolized by the CYP3A4 isoenzyme (about 95%), while the CYP2D6 isoenzyme plays only a minor role.

The clearance of bisoprolol is determined by the balance between excretion by the kidneys in unchanged form (about 50%) and metabolism in the liver (about 50%) to metabolites that are also excreted by the kidneys. Since the excretion occurs through the kidneys and liver in the same volume, dose adjustment is not required for patients with mild to moderate hepatic or renal insufficiency. The total clearance is 15 l / h. T_1/2 - 10-12 hours —

• Antihypertensive agent combined (β₁- adrenoblocker selective blocker of "slow" calcium channels (BMCC) [Beta-blockers in combinations]
• Antihypertensive agent combined (β₁- adrenoblocker selective blocker of "slow" calcium channels (BMCC) [Calcium channel blockers in combinations]

Amlodipine

CYP3A4 inhibitors: Amlodipine should be used with caution in combination with CYP3A4 inhibitors.

Strong and moderate CYP3A4 inhibitors (protease inhibitors such as indinavir, saquinavir and ritonavir, azole antifungal agents such as fluconazole and itraconazole, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may increase the concentration of amlodipine in the blood plasma to clinically significant values. These changes may be more pronounced in older patients, which requires clinical monitoring of the amlodipine concentration and dose adjustment if necessary.

Inducers of CYP3A4: concomitant use with inducers of CYP3A4 (including rifampicin, St. John's wort) may lead to a decrease in the concentration of amlodipine in the blood plasma.

Amlodipine should be used with caution simultaneously with CYP3A4 inducers.

Dantrolene (infusion): the animals were observed lethal ventricular fibrillation and cardiovascular collapse in Association with hyperkalemia after administration of verapamil and dantrolene V/V.

Due to the risk of hyperkalemia, it is not recommended to co-administer BCC, such as amlodipine, during the treatment of malignant hyperthermia and in patients predisposed to malignant hyperthermia.

Tacrolimus: There is a risk of an increase in the level of tacrolimus in the blood when taken together with amlodipine, but the pharmacokinetic mechanism of this interaction is not fully understood. To avoid the toxicity of tacrolimus, in patients undergoing treatment, it is necessary to monitor its level in the blood and select the dose of tacrolimus if necessary.

Cyclosporine: The possibility of monitoring the level of cyclosporine in patients who have undergone a kidney transplant while taking amlodipine should be considered, and the dose of cyclosporine should be reduced if necessary.

Simvastatin: concomitant use with amlodipine may lead to an increase in the concentration of simvastatin in the blood plasma. Co-administration of amlodipine at a dosage of 10 mg with 80 mg of simvastatin resulted in a 77% increase in the effect of simvastatin compared to simvastatin alone. The dose of simvastatin should be limited to 20 mg once a day in patients receiving amlodipine.

Taking amlodipine with grapefruit or grapefruit juice is not recommended due to the possible increase in the bioavailability of amlodipine, which leads to the effect of lowering high blood pressure.

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 agents.

Amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, ethanol (beverages containing alcohol), warfarin.

Bisoprolol

Not recommended combinations

BCC, such as verapamil and to a lesser extent, diltiazem, when used simultaneously with bisoprolol, can lead to a decrease in the contractility of the myocardium, a pronounced decrease in blood pressure and a violation of AV conduction. In particular, intravenous administration of verapamil to patients taking beta-blockers can lead to severe hypotension and AV block.

Antihypertensive medications Central action (such as clonidine, methyldopa, moxonidine, rilmenidine) when used concomitantly with bisoprolol can lead to a decrease in heart rate and cardiac output, as well as to vasodilation due to a decrease in central sympathetic tone. Abrupt withdrawal, especially before the withdrawal of beta-blockers, may increase the risk of developing rebound hypertension.

Combinations that require caution

BCC, derivatives of dihydropyridines (e.g. nifedipine), concomitant use with bisoprolol may increase the risk of hypotension.

In patients with CHF, the risk of subsequent deterioration of the contractile function of the heart cannot be excluded.

Class I antiarrhythmic drugs (for example, quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone) may reduce AV conduction and myocardial contractility when used concomitantly with bisoprolol.

Class III antiarrhythmic drugs (for example, amiodarone) may increase the violation of AV conduction.

Parasympathomimetics when used concomitantly with bisoprolol, they may increase the violation of AV conduction and increase the risk of developing bradycardia.

The effect of beta-blockers for topical use (for example, eye drops for the treatment of glaucoma) , it can enhance the systemic effects of bisoprolol (lowering blood pressure, reducing heart rate).

Hypoglycemic effect insulin or hypoglycemic agents for oral administration may be increased. Blockade of beta-blockers can mask the signs of hypoglycemia, particularly tachycardia. Such interactions are more likely when using non-selective beta-blockers.

Means for general anesthesia may weaken reflex tachycardia and increase the risk of hypotension (see "Special instructions").

Cardiac glycosides When used concomitantly with bisoprolol, it can lead to an increase in AV conduction time and the development of bradycardia.

NSAIDs may reduce the antihypertensive effect of bisoprolol.

Concomitant use of bisoprolol with beta-adrenomimetics (for example, isoprenaline, dobutamine) may lead to a decrease in the effect of both drugs.

The combination of bisoprolol with adrenomimetics that affect beta-and alpha-adrenoreceptors (for example, norepinephrine, epinephrine) can enhance the vasoconstrictor effects of these drugs that occur with the participation of alpha-adrenoreceptors, 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 need to be considered

Mefloquine concomitant use with bisoprolol may increase the risk of 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 slightly shortens T_1/2 bisoprolol. As a rule, no dose adjustment is required.

Derivatives of ergotamine when used concomitantly with bisoprolol, the risk of developing peripheral circulatory disorders increases.