Amlodipine + Bisoprolol - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Calcium channel blockers

Beta-blockers

Included in the formulation

Amlodipine + Bisoprolol

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NORTH STAR, CJSC Russia

Concor® AM

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Merck KGaA Germany

Niperten® Combi

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KRKA-RUS, LLC Russia

АТХ:

C.07.F.B Selective beta-1 blockers in combination with other antihypertensive drugs

Pharmacodynamics:

Combined antihypertensive drug. It has pronounced antihypertensive and antianginal effects due to the complementary action of two active substances: slow calcium channel blocker - amlodipine and selective beta₁adrenoblocker - bisoprolol.

Amlodipine

Amlodipine blocks the calcium channels, reduces the transmembrane transition of calcium ions into the cell (mostly in the smooth muscle cells of the vessels than in the cardiomyocytes).

The antihypertensive effect of amlodipine is due to a direct relaxing effect on the smooth muscle cells of the vessels, 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. Expansion of peripheral arterioles reduces oVascular peripheral resistance, that is, afterload. Because the amlodipine does not cause reflex tachycardia, energy consumption and oxygen myocardium decreases.

2. Expansion of large coronary arteries and coronary arterioles improves the supply of oxygen to both normal and ischemic zones of the myocardium. Due to these effects, the supply of oxygen to the myocardium improves, even with spasm of the coronary arteries (Prinzmetal angina or unstable angina). In patients with hypertension, taking the drug 1 time per day causes a clinically significant decrease in blood pressure in the prone position and standing during 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, taking the drug once a day increases the total time of exercise, the time before the onset of an attack of angina, as well as the time to a significant decrease in the ST interval, and also reduces the incidence of angina attacks and the need for sublingual administration of nitroglycerin.

There was no negative effect of amlodipine on the exchange of blood plasma lipids, blood glucose and serum uric acid.

Bisoprolol

Bisoprolol - selective beta₁- adrenoblocker, without its own sympathomimetic activity, does not possess membrane-stabilizing action.

He has only a slight affinity for beta₂-adrenoreceptors of smooth muscles of bronchi and vessels, as well as to beta₂adrenoreceptors involved in the regulation of metabolism. Consequently, bisoprolol in general, does not affect the resistance of the respiratory tract and the metabolic processes involved beta₂-adrenoceptors.

Selective action of the drug on beta₁-adrenoceptors persists 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 per day, its therapeutic effect persists for 24 hours due to a 10-12-hour half-life from the blood plasma. Typically, the maximum antihypertensive effect is achieved 2 weeks after the start of treatment.

Bisoprolol reduces the activity of the sympathoadrenal system, blocking beta₁-adrenoceptors of the heart.

With a single admission in patients with coronary heart disease without signs of chronic heart failure bisoprolol reduces the heart rate, reduces the shock volume of the heart and, as a result, reduces the ejection fraction and the need for myocardium in oxygen. With prolonged therapy, initially increased total peripheral vascular resistance is reduced. Reduction of renin activity in blood plasma is considered as one of the components of antihypertensive action of beta-blockers.

Pharmacokinetics:

Amlodipine

Suction

Amlodipine is well absorbed after ingestion. C_maxin blood plasma is observed after 6-12 hours. Taking the drug together with food does not affect its absorption. Absolute bioavailability is 64-80%.

Distribution

Visible V_dis 21 l / kg. C_ssin blood plasma (5-15 ng / ml) is achieved 7-8 days after the start of the drug.

Research in vitro showed that circulating amlodipine approximately 93-98% is associated with blood plasma proteins.

Metabolism and excretion

Amlodipine undergoes intensive metabolism in the liver. Approximately 90% of the accepted 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 plasma concentration is biphasic. Final half-lifeis approximately 35-50 hours, which allows you to enter the drug 1 time per day. The total clearance is 7 ml / min / kg (25 l / h in a patient with a body weight of 60 kg). In elderly patients, it is 19 l / h.

Pharmacokinetics in special clinical cases

In elderly patients and patients with renal insufficiency, there was no significant change in the pharmacokinetics of amlodipine.

Due to lower clearance, patients with hepatic insufficiency should be given a lower initial dose.

Bisoprolol

Suction

Bisoprolol is almost completely (more than 90%) absorbed from the digestive tract. Its bioavailability due to insignificant metabolism at the "first passage" through the liver (at about 10%) is about 90%
after ingestion. Eating does not affect bioavailability. Bisoprolol demonstrates linear kinetics, and its concentrations in the blood plasma are proportional to the dose taken in the range of 5 to 20 mg. C_max in blood plasma is achieved in 2-3 hours.

Distribution

Bisoprolol is distributed quite widely. V_dis 3.5 l / kg. Binding to plasma proteins reaches about 30%.

Metabolism

Metabolized by 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. Data obtained as a result of experiments with microsomes of human liver in vitro, show that bisoprolol is metabolized primarily with the help of the CYP3A4 isoenzyme (about 95%), and the CYP2D6 isoenzyme plays only a minor role.

Excretion

Bisoprolol clearance is determined by the balance between excretion by the kidneys in an unchanged form (about 50%) and metabolism in the liver (about 50%) to metabolites that are also excreted by the kidneys. The total ground clearance is 15 l / h. The half-life is 10-12 hours.

Indications:

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

ICD-10

IX.I10-I15.I10 Essential [primary] hypertension

Contraindications:

Severe arterial hypotension (systolic blood pressure less than 100 mm mercurypillar); shock (including cardiogenic); age under 18 years (effectiveness and safety not established); hypersensitivity to amlodipine, other dihydropyridine derivatives, bisoprolol and / or any of the excipients.

Carefully:

X(including non-ischemic etiology of NYHA class III-IV functional class), hepatic insufficiency, renal failure, hyperthyroidism, diabetes mellitus with significant fluctuations in blood glucose concentration, AV-blockade of I degree, angina of Prinzmetal, occlusive diseases of peripheral arteries , psoriasis (including history), fasting (strict diet), pheochromocytoma (with the simultaneous use of alpha-adrenoblokatorov), bronchial asthma and chronic obstructive b lung disease, simultaneous desensitizing therapy, general anesthesia, elderly age, arterial hypotension, type 1 diabetes, aortic stenosis, mitral stenosis, acute myocardial infarction (after the first 28 days).

Pregnancy and lactation:

Amlodipine

AT experimental research fetotoxic and embryotoxic effects of the drug are not established, but use in pregnancy is possible only if the benefit to the mother exceeds the potential risk to the fetus.

There is no evidence of excretion of amlodipine in breast milk. However, it is known that others blockers of slow calcium channels - derivatives of dihydropyridine - excreted in breast milk. In this connection, if it is necessary to prescribe amlodipine during lactation, the question of stopping breastfeeding should be resolved.

Bisoprolol

The use of bisoprolol in pregnancy is possible only if the intended benefit to the mother exceeds the potential risk to the fetus. Beta-adrenoblockers reduce blood flow in the placenta and can affect the development of the fetus.

Blood flow in the placenta and uterus should be monitored, and the growth and development of the unborn child should be monitored, and alternative therapies should be considered if pregnancy and / or fetus are undesirable.

You should carefully examine the newborn after delivery.In the first three days of life, bradycardia and hypoglycemia may occur.

There is no data on the isolation of bisoprolol with breast milk. Therefore, taking the drug is not recommended for women during breastfeeding. If bisoprolol is required during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Tablets for oral administration. Tablets should be taken in the morning, regardless of food intake, without chewing.

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

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 substances that make up the drug.

Treatment with the drug is usually a long-term therapy.

Have patients with impaired liver function excretion of amlodipine may be delayed. A special dosing regimen for this group of patients is not defined, but the drug should be given with caution in this case.

For patients with severe hepatic impairment the maximum daily dose of bisoprolol is 10 mg.

Patients with impaired renal function light or moderate correction of the dosing regimen, as a rule, is not required. Amlodipine not output by dialysis. Patients undergoing dialysis should be prescribed amlodipine with extreme caution.

For patients with severe renal dysfunction (creatinine clearance less than 20 ml per minute) the maximum daily dose of bisoprolol is 10 mg.

To patients of advanced age the drug can be administered in usual doses. Caution is required only when the dose is increased.

The drug is not recommended for use in children and adolescents under the age of 18 in the absence of data on efficiency and safety.

Treatment should not be stopped abruptly, as this may lead to a temporary deterioration in the clinical condition. Especially, treatment should not be abruptly discontinued in patients with ischemic heart disease. A gradual dose reduction is recommended.

Side effects:

Amlodipine

On the part of the hematopoiesis system: very rarely - leukopenia, thrombocytopenia.

From the side of metabolism: very rarely - hyperglycemia.

From the side of the psyche: infrequently - insomnia, mood changes (including anxiety), depression; rarely confusion.

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

From the side of the organ of vision: infrequently - impaired vision (including diplopia).

From the side of the hearing organ and labyrinthine disorders: infrequently, noise in the ears.

From the digestive system: often - nausea, abdominal pain; infrequently - a change in the mode of defecation (including constipation or diarrhea), indigestion, dryness of the oral mucosa; very rarely - gastritis, gingival hyperplasia, pancreatitis.

From the liver and bile ducts: very rarely - hepatitis (in most cases with cholestasis), jaundice (in most cases with cholestasis).

From the cardiovascular system: often - a feeling of palpitations, flushes of blood to the face; infrequent - marked decrease in blood pressure; very rarely - myocardial infarction, arrhythmia (bradycardia, ventricular tachycardia, atrial fibrillation), vasculitis.

From the respiratory system: infrequently - shortness of breath, rhinitis; very rarely - cough.

From the urinary system: infrequently - pollakiuria, painful urge to urinate, nocturia.

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

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

Allergic reactions: very rarely - angioedema, urticaria, angioedema.

From the skin and subcutaneous tissues: infrequently - alopecia, purpura, discoloration, increased sweating, itching, rash, exanthema; very rarely - multi-form exudative erythema, exfoliative dermatitis, Stevens-Jones syndromeabouton, photosensitivity.

Common violations: often - peripheral edema, increased fatigue; infrequently - chest pain, asthenia, pain, general malaise.

Laboratory and instrumental data: infrequently - weight gain, weight loss; very rarely - an increase in the activity of hepatic enzymes in most cases with cholestasis.

Bisoprolol

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

From the side of the psyche: infrequently - depression; rarely - hallucinations, nightmares.

From the nervous system: often - headache, dizziness; infrequently - insomnia; rarely - faint.

From the side of the organ of vision: rarely - a decrease in lacrimation (should be considered when wearing contact lenses); very rarely - conjunctivitis.

From the side of the hearing organ and labyrinthine disorders: rarely - hearing impairment.

From the cardiovascular system: often - a feeling of cold or numbness in the limbs, a marked decrease in blood pressure; infrequently - a violation of AV-conduction, bradycardia, exacerbation of symptoms of chronic heart failure, orthostatic hypotension.

From the respiratory system: infrequently bronchospasm in patients with bronchial asthma or airway obstruction in anamnesis; rarely allergic rhinitis.

From the digestive system: often - nausea, vomiting, diarrhea, constipation.

From the liver and bile ducts: rarely - hepatitis.

From the skin and subcutaneous tissues: rarely - hypersensitivity reactions, such as pruritus, 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: infrequently - muscle weakness, muscle cramps.

From the genitals and the breast: rarely - impotence.

General disorders: often - increased fatigue; infrequent is exhaustion.

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

Overdose:

Amlodipine

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

Treatment: gastric lavage, the appointment of activated charcoal, maintenance of cardiovascular function, control of heart and lung function, elevated limb position, control volume of circulating blood and diuresis. Intensive symptomatic therapy. To restore the vascular tone, the use of vasoconstrictive drugs (in the absence of contraindications to their use); to eliminate the effects of calcium channel blockade - intravenous calcium gluconate. Hemodialysis is not effective.

Bisoprolol

Symptoms: AV-blockade, pronounced bradycardia, marked decrease in blood pressure, bronchospasm, acute heart failure and hypoglycemia. The sensitivity to a single dose of a high dose of bisoprolol varies greatly among individual patients, and presumably patients with chronic heart failure are highly sensitive.

Treatment: In case of an overdose, first of all, it is necessary to stop taking the drug and begin supporting symptomatic therapy. With severe bradycardia - intravenous atropine. If the effect is insufficient, with caution, you can enter a drug that has a positive chronotropic effect. Sometimes it may be necessary to temporarily set up an artificial pacemaker.

With a marked decrease in blood pressure - intravenous injection of plasma-substituting solutions and vasopressor preparations. Intravenous administration of glucagon may also be indicated.

With AV blockade, patients should be under constant observation and receive treatment with beta-adrenomimetics, such as epinephrine. If necessary - staging an artificial pacemaker.With exacerbation of chronic heart failure, intravenous diuretics, drugs with a positive inotropic effect, and vasodilators.

When bronhospazme - the appointment of bronchodilators, including beta₂adrenomimetics and / or aminophylline.

When hypoglycemia - intravenous dextrose (glucose).

Bisoprolol is practically not excreted in dialysis.

Interaction:

Amlodipine

The simultaneous use of amlodipine with thiazide diuretics, beta-adrenoblockers, long-acting nitrates, sublingual preparations of nitroglycerin, nonsteroidal anti-inflammatory drugs, antibiotics and hypoglycemic agents for oral administration is considered safe.

Caution should be applied amlodipine simultaneously with inhibitors of CYP3A4. Although no adverse events related to such an interaction were reported.

Simultaneous application with inhibitors of CYP3A4 (including rifampicin, St. John's wort pitted) can lead to a decrease in the concentration of amlodipine in the blood plasma. Caution should be applied amlodipine simultaneously with inductors CYP3A4.

Grapefruit juice, cimetidine, aluminum / magnesium (in the composition 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 performance.

Bisoprolol

Unrecommended combinations

Blockers of slow calcium channels type verapamil and, to a lesser extent, diltiazem, with simultaneous application with bisoprolol may lead to a decrease in the contractility of the myocardium, expressed by a 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 arterial hypotension and AV blockade.

Hypotensive agents of central action (such as clonidine, methyldopa, moxonidine, rilmenidine) with simultaneous application with bisoprolol may lead to a decrease in the heart rate and a decrease in cardiac output, as well as to vasodilation due to a decrease in the central sympathetic tone.Abrupt cancellation, especially before the abolition of beta-blockers may increase the risk of developing "ricochet" hypertension.

Combinations that require caution

Blockers of slow calcium channels derivatives of dihydropyridine (for example, nifedipine) with simultaneous application with bisoprolol may increase the risk of developing arterial hypotension. In patients with chronic heart failure, the risk of subsequent deterioration of the contractile function of the heart can not be ruled out.

Antiarrhythmic drugs of the first class (for example, quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone) with simultaneous application with bisoprolol may reduce AV-conduction and contractility of the myocardium. Antiarrhythmic drugs of the III class (for example, amiodarone) can enhance the disturbance of AV-conduction.

Parasympatomimetics with simultaneous application with bisoprolol may increase the disturbance of AV conduction and increase the risk of developing bradycardia.

The action of beta-blockers for topical application (eg, eye drops for the treatment of glaucoma) can enhance the systemic effects of bisoprolol (lowering blood pressure, decreasing heart rate).

The hypoglycemic effect of insulin or hypoglycemic agents for oral ingestion may be enhanced. Symptoms of hypoglycemia - in particular tachycardia - can be masked. Such interactions are more likely when using nonselective beta-blockers.

Means for conducting general anesthesia can weaken reflex tachycardia and increase the risk of developing arterial hypotension.

Cardiac glycosides with simultaneous application with bisoprolol may lead to an increase in the timing of the impulse and to the development of a bradycardia.

Nonsteroidal anti-inflammatory drugs can reduce the antihypertensive effect of bisoprolol.

The simultaneous use of bisoprolol with beta-adrenomimetics (eg, isoprenaline, dobutamine) can lead to a decrease in the effect of both drugs.

The combination of bisoprolol with adrenomimetics that affect alpha and beta-adrenergic receptors (for example, norepinephrine, epinephrine) may enhance the vasoconstrictor effects of these agents that occur with alpha-adrenergic receptors, leading to an increase in blood pressure.Such interactions are more likely when using nonselective beta-blockers.

Hypotensive drugs, as well as other agents with possible antihypertensive effect (for example, tricyclic antidepressants, barbiturates, phenothiazines) can enhance the antihypertensive effect of bisoprolol.

Combinations that need to be considered

Mefloquine with simultaneous application with bisoprolol may increase the risk of developing bradycardia.

MAO inhibitors (with the exception of MAO B inhibitors) can enhance the antihypertensive effect of beta-blockers. Simultaneous application can also lead to the development of hypertensive crisis.

Rifampicin slightly shortens the half-life of bisoprolol. As a rule, dose adjustment is not required.

Derivatives of ergotamine with simultaneous application with bisoprolol increase the risk of peripheral circulatory disturbance.

Special instructions:

Amlodipine

Patients with heart failure should take amlodipine carefully. In patients with heart failure III-IV stage according to the classification of NYHA amlodipine increases the risk of pulmonary edema, which is not associated with worsening symptoms of chronic heart failure.

Bisoprolol

The discontinuation of bisoprolol treatment should not be sudden, especially in patients with coronary heart disease, unless there is clear evidence of drug withdrawal. Sudden abolition of bisoprolol may lead to a temporary worsening of cardiac pathology. Bisoprolol should be administered with extreme caution to patients with hypertension or angina pectoris, in combination with heart failure. As in the case of other beta-blockers, bisoprolol can cause an increase in sensitivity to allergens and increase anaphylactic reactions, so care must be taken with simultaneous desensitizing therapy. The use of epinephrine can not always produce the expected therapeutic effect.

When bisoprolol is used, the symptoms of hyperthyroidism may be masked.

In patients with pheochromocytoma bisoprolol should be appointed only after blockade of alpha-adrenergic receptors.

Before conducting general anesthesia, the anesthetist should be informed of the patient's admission of beta-blockers.If it is necessary to cancel the beta-blocker before surgery, this should be done gradually and completed approximately 48 hours before anesthesia.

With bronchial asthma or chronic obstructive pulmonary disease, simultaneous application of bronchodilating agents is indicated. Patients with bronchial asthma may have an increase in airway resistance, which requires a higher dose of beta₂-adrenomimetics.

Impact on the ability to drive vehicles and manage mechanisms

During the period of drug treatment, care should be taken in the management of vehicles and work with technically complex mechanisms.

Instructions

Amlodipine + Bisoprolol (Amlodipinum + Bisoprololum)