Bisoprolol AML tablets 5 mg+5 mg, 30 pcs.

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

Mechanism of action of amlodipine:

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

Antihypertensive effect of amlodipine is caused by direct relaxant action on vascular smooth muscle cells which leads to decrease of peripheral vascular resistance. The mechanism of antianginal action is not fully understood; it may be related to the following two effects:

1. Dilation of peripheral arterioles reduces total peripheral resistance, i.e., postload Because amlodipine does not cause reflex tachycardia, myocardial energy and oxygen consumption are reduced.

1 Dilation of large coronary arteries and coronary arterioles improves oxygen supply to both normal and ischemic areas of the myocardium. These effects improve the oxygen supply to the myocardium, even in cases of coronary artery spasm (Prinzmetal’s angina or unstable angina).

In patients with arterial hypertension once daily administration of the drug causes clinically significant reduction of BP in “lying” and “standing” position during the whole 24-hour interval between doses of the drug Due to slow development of antihypertensive effect of amlodipine it does not cause acute arterial hypotension. In patients with angina pectoris, taking the drug once a day increases total time of physical activity, time to angina attack and time to significant decrease of ST interval, and decreases the frequency of angina attacks and the need for sublingual administration of nitroglycerin. No negative effect of amlodipine on plasma lipid, blood glucose and serum uric acid metabolism has been found.

The mechanism of action of bisoprolol:

Bisoprololol is a selective beta1-adrenoblocker with no sympathomimetic activity of its own and no membrane-stabilizing effects.

It has only a minor affinity for beta2-adrenoreceptors of bronchial and vascular smooth muscle as well as for beta2-adrenoreceptors involved in metabolic regulation Therefore, bisoprololol does not generally affect the airway resistance and metabolic processes in which beta2-adrenoreceptors are involved.

The selective effect of the drug on beta1-adrenoceptors is maintained beyond the therapeutic range. Bisoprolol has no significant negative inotropic effect;

The maximal effect of the drug is reached 3-4 hours after oral administration. Even when bisoprololol is administered once daily its therapeutic effect is maintained for 24 hours due to 10-12 hour blood plasma elimination half-life.

As a rule, the maximal antihypertensive effect is achieved 2 weeks after the beginning of treatment.

Bisoprolol reduces sympathoadrenal system (SAS) activity by blocking the beta1-adrenoreceptors of the heart.

On single oral administration in patients with coronary heart disease (CHD) without signs of chronic heart failure (CHF), bisoprolol decreases heart rate (HR), reduces heart stroke volume and, consequently, decreases ejection fraction and myocardial oxygen demand. During long-term therapy, initially increased total peripheral vascular resistance (TPR) decreases. Reduction of plasma renin activity is considered to be a component of the hypotensive effect of beta-adrenoblockers. Amlodipine pharmacokinetics:

Intake:

Amlodipine is well absorbed after oral administration. The maximum concentration in blood plasma is observed after 6-12 hours. Absorption of the drug with food has no effect on its absorption. Absolute bioavailability is 64 – 80%.

Distribution:

Visible volume of distribution is 21 l/kg. The equilibrium plasma concentration (5-15 ng/ml) is reached 7-8 days after initiation of the drug.

In vitro studies have shown that circulating amlodipine is approximately 93-98% bound to plasma proteins.

Metabolism and excretion:

Amlodipine undergoes intensive metabolism in the liver. Approximately 90% of the dose taken is converted to inactive pyridine derivatives. Approximately 10% of the administered dose is excreted unchanged in the urine. Approximately 60% of inactive metabolites are excreted by the kidneys and 20-25% via the intestine. Decrease in plasma concentrations is biphasic. Final elimination half-life is about 35-50 hours, which allows administering the drug once a day. Total clearance is 7 ml/min/kg (25 l/h in patients weighing 60 kg). In elderly patients it is 19 l/hour.

In elderly patients and patients with renal insufficiency no significant changes in pharmacokinetics of amlodipine have been observed. Due to decreased clearance, patients with hepatic impairment should be prescribed lower initial doses.

Amlodipine penetrates the blood-brain barrier. Bisoprolol:

Introduction. Bisoprolol is almost completely (more than 90%) absorbed from the gastrointestinal tract. Its bioavailability is about 90% after oral administration due to insignificant metabolism “during the first passage” through liver (about 10%). Food intake has no effect on bioavailability. Bisoprolol exhibits linear kinetics, with plasma concentrations proportional to the dose taken, ranging from 5 to 20 mg. The maximum plasma concentration is reached after 2 to 3 hours.

Distribution. Bisoprolol is distributed quite widely. The volume of distribution is 3.5 l/kg. The binding to blood plasma proteins reaches about 30%.

Metabolism. Metabolized by the oxidative pathway without subsequent conjugation. All metabolites are polar (water-soluble) and are excreted by the kidneys. The major metabolites found in blood plasma and urine have no pharmacological activity. The data obtained from in vitro experiments with human liver microsomes show that bisoprolol is metabolized primarily by the CYP3A4 isoenzyme (approximately 95%) and the CYP2D6 isoenzyme plays only a minor role.

Elimination. Bisoprolol clearance is determined by a balance between excretion by the kidneys unchanged (about 50%) and metabolism in the liver (about 50%) to metabolites, which are also excreted by the kidneys. Total clearance is 15 l/hour. The elimination half-life is 10-12 hours.

Indications

Active ingredient

Composition

1 tablet contains:

dosage 5 mg + 5 mg:

acting ingredients:

5 mg amlodipine besylate (in terms of amlodipine) and 5 mg bisoprolol fumarate:

complementary substances:

Microcrystalline cellulose, 132.5 mg;

Sodium carboxymethyl starch, 5.0 mg;

magnesium stearate – 1.5 mg;

colloidal silica (aerosil anhydrous) – 1.0 mg.

Interaction

As for amlodipine:

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

CYP3A4 inhibitors: Caution should be exercised when using amlodipine concomitantly with CYP3A4 inhibitors.

Powerful and moderate CYP3A4 inhibitors (e.g., protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may increase plasma concentrations of amlodipine to clinically significant levels.

CYP3A4 inducers: Concomitant use with CYP3A4 inducers (including rifampicin, St. John’s Wort) may lead to decreased plasma concentrations of amlodipine. Caution should be exercised when using amlodipine concomitantly with CYP3A4 inducers.

Simvastatin: Concomitant use with amlodipine may lead to increased plasma concentrations of simvastatin. Patients taking amlodipine are not recommended to use simvastatin in dose more than 20 mg per day.

Grapefruit juice, cimetidine, aluminum/magnesium (as part of antacids) and sildenafil have no effect on the pharmacokinetics of amlodipine.

Amlodipine may increase the antihypertensive effect of other hypotensive agents.

Amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, ethanol (drinks containing alcohol), warfarin or cyclosporine. Amlodipine has no effect on laboratory parameters.

On bisoprolol:

Not recommended combinations

Slow calcium channel blockers (SCBs) such as verapamil and, to a lesser extent, diltiazem, when used concomitantly with bisoprolol can lead to decreased myocardial contractility, markedly lower BP and impaired AV conduction. In particular, intravenous administration of verapamil in patients taking beta-adrenoblockers can lead to severe arterial hypotension and AV blockade. Hypotensive agents of central action (such as clonidine, methyldopa, moxonidine, rilmenidine) when concomitantly used with bisoprolol may lead to a reduced HR and decreased cardiac output, as well as to vasodilation due to the reduction of central sympathetic tone. Abrupt withdrawal, especially prior to beta-adrenoblocker withdrawal, may increase the risk of “ricochet” arterial hypertension.

Combinations requiring caution BMCC dihydropyridine derivatives (e.g., nifedipine) when used concomitantly with bisoprolol may increase the risk of arterial hypotension. In patients with CHF, the risk of subsequent deterioration of cardiac contractility cannot be excluded. Class I antiarrhythmic agents (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone) in concomitant use with bisoprolol may decrease AV conduction and myocardial contractility.

The antiarrhythmic agents of class III (e.g., amiodarone) may increase AV conduction impairment.

Parasympathomimetics, when used concomitantly with bisoprolol, may exacerbate AV conduction disturbances and increase the risk of bradycardia.

The effects of beta-adrenoblockers for topical use (e.g., eye drops to treat glaucoma) may increase the systemic effects of bisoprololol (decreased BP, slower heart rate). Hypoglycemic effect of insulin or hypoglycemic agents for oral administration may increase. Signs of hypoglycemia – in particular tachycardia – may be masked. Such interactions are more likely when using non-selective beta-adrenoblockers. Means for general anesthesia may attenuate reflex tachycardia and increase the risk of arterial hypotension (see section “Special Precautions”).

The cardiac glycosides, when used concomitantly with bisoprolol, may lead to prolongation of the pulse conduction time and development of bradycardia.

Concomitant use of bisoprolol with beta-adrenomimetics (e.g., isoprenaline, dobutamine) may decrease the effect of both drugs.

The combination of bisoprolol with adrenomimetics affecting beta- and alpha-adrenoreceptors (e.g. norepinephrine, epinephrine) may enhance the vasoconstrictor effects of these agents arising from alpha-adrenoreceptors, leading to increased BP. Such interactions are more likely when using non-selective beta-adrenoblockers.

Hypotensive agents, as well as other agents with possible antihypertensive effects (e.g., tricyclic antidepressants, barbiturates, phenothiazines) may increase the antihypertensive effect of bisoprolol.

Combinations to consider

Mefloquine when used concomitantly with bisoprolol may

increase the risk of bradycardia.

MAO inhibitors (except MAO B inhibitors) may increase the antihypertensive effect of beta-adrenoblockers. Concomitant use may also lead to the development of a hypertensive crisis. Rifampicin slightly shortens the half-life (T,/2) of bisoprolol. Dose adjustment is generally not required Ergotamine derivatives when used concomitantly with bisoprololol increase the risk of peripheral circulatory disorders.

Directions for use

The recommended daily dose is 1 tablet a day of a certain dosage. Selection and titration of the dose is performed individually for each patient by the physician while prescribing monocomponent preparations containing active ingredients of Bisoprolol AML.

The duration of treatment

The treatment with Bisoprolol AML is usually long-term therapy.

Hepatic impairment

In patients with hepatic impairment the excretion of amlodipine may be delayed. A specific dosing regimen has not been defined for this group of patients, but the drug should be prescribed with caution in this case. For patients with severe hepatic impairment the maximum daily dose of bisoprololol is 10 mg Renal impairment

Patients with mild to moderate renal impairment do not usually require dosing adjustments. Amlodipine is not excreted with dialysis. Patients undergoing dialysis should be prescribed amlodipine with special caution.

In patients with significant renal impairment (creatinine clearance (CK) less than 20 ml/min), the maximum daily dose of bisoprolol is 10 mg.

Elderly patients

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

Children

The drug is not recommended for use in children under 18 years of age due to lack of efficacy and safety data. Treatment should not be stopped abruptly, because it may cause a temporary worsening of the clinical condition. Especially, treatment should not be stopped abruptly in patients with IBD A gradual reduction of the dose is recommended.

Special Instructions

Amlodipine

In patients with hepatic impairment, the T|/2 of amlodipine is prolonged. Caution should be exercised when prescribing the drug in these patients and “hepatic” enzyme activity should be regularly monitored.

When prescribing amlodipine in patients with chronic heart failure caution is necessary In patients with CHF (including nonischemic aetiology of NYHA functional class III-IV), amlodipine increases risk of pulmonary edema, which is not associated with aggravation of symptoms of CHF course.

Body weight and table salt intake should be controlled during amlodipine therapy, and appropriate dietary prescription is indicated. It is necessary to maintain oral hygiene and see a dentist (to prevent soreness, bleeding and gum hyperplasia).

In In In Vitro Fertilization (IVF), reversible biochemical changes in the sperm head have been observed in a few cases of IVF treatment with BICC, resulting in impaired sperm function.

In unsuccessful IVF attempts and when other causes of infertility are excluded, the possibility of effects on sperm cells of BICCs should be taken into account when using them.

Bisoprolol

Monitoring of patients taking bisoprolol should include measurement of HR and BP, ECG, determination of blood glucose concentration in diabetic patients (once every 4-5 months). In elderly patients it is recommended to monitor kidney function (once every 4-5 months).

The patient should be trained in the method of heart rate calculation and instructed to consult a physician if the heart rate is less than 60 bpm. An external respiratory function study in patients with a history of poor bronchopulmonary function is recommended prior to initiating treatment. Patients who wear contact lenses should take into account that against the background of the drug treatment there may be decrease of lacrimal fluid production.

When using bisoprololol in patients with pheochromocytoma, there is a risk of paradoxical arterial hypertension (if effective a-adrenoreceptor blockade has not been previously achieved). In hyperthyroidism, bisoprolol may mask certain clinical signs of hyperthyroidism (e.g., tachycardia). Abrupt withdrawal of the drug in patients with hyperthyroidism should be avoided to avoid worsening of symptoms.

When clonidine is used simultaneously its administration can be stopped only after several days after bisoprolol withdrawal. It is possible to increase the severity of hypersensitivity reactions and lack of effect of usual doses of epinephrine (adrenaline) against the background of a history of allergy aggravation.

If it is necessary to perform planned surgical treatment, bisoprololol should be discontinued 48 hours before general anesthesia. If the patient has taken bisoprolol before surgical intervention, the patient should choose a general anesthesia drug with minimal negative inotropic effect.

The reciprocal activation of the vagus nerve can be managed with intravenous atropine (1-2 mg).

Drugs that deplete catecholamine depots (including reserpine) can potentiate the effects of P-adrenoblockers, so patients taking these combinations of drugs should be monitored closely for markedly lower BP or bradycardia.

Patients with bronchospastic disorders may be treated with caution with cardioselective p-adrenoblockers if other hypotensive agents are intolerant and/or ineffective with concomitant use of bronchodilators. Against the background of taking p-adrenoblockers in patients with concomitant bronchial asthma, airway resistance may increase. If the dose of bisoprolol is exceeded, such patients are at risk of bronchospasm. If bradycardia (HR less than 60 beats/min), marked BP decrease (systolic BP less than 100 mm Hg), AV blockade are detected in patients, the dose should be reduced or treatment should be stopped.

It is recommended to discontinue bisoprolol therapy if depression develops.

Bisoprolol should not be stopped abruptly because of the risk of severe arrhythmias and myocardial infarction. Withdrawal of the drug is done gradually, reducing the dose over 2 weeks or more (reduce the dose by 25% in 34 days). The drug should be discontinued before blood and urine concentrations of catecholamines, normetanephrine, vanillylmindalic acid, and antinuclear antibody titers are investigated.

In smokers, the efficacy of p-adrenoblockers is lower.

Synopsis

Contraindications

Ampodipine:

Instable angina (except for Prinzmetal angina);

Hemodynamically unstable heart failure after myocardial infarction;

Clinically significant aortic stenosis.

Bisoprolol:

– acute heart failure or chronic heart failure (CHF) in decompensation requiring inotropic therapy;

– Atrioventricular (AV) block of II and III degree, without pacemaker;

– sinus node weakness syndrome (SNS);

– sinoatrial block;

– marked bradycardia (HR less than 60 beats/min);

– severe bronchial asthma or chronic obstructive pulmonary disease (COPD);

– severe peripheral arterial circulatory disorders or Raynaud’s syndrome;

– pheochromocytoma (without concomitant use of alpha-adrenoblockers);

– metabolic acidosis;

On the combination amlodipine/bisoprolol:

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

– severe arterial hypotension (systolic BP less than 100 mm Hg.

– shock (including cardiogenic);

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

WARNING

CRC (including non-ischemic etiology of NYHA functional class III-IV), hepatic insufficiency, renal insufficiency, hyperthyroidism, diabetes mellitus with significant blood glucose fluctuations, AV blockade of degree I, Prinzmetal angina, peripheral arterial occlusive disease, psoriasis (in including history), fasting (strict diet), pheochromocytoma (with concomitant use of alpha-adrenoblockers), bronchial asthma and COPD, concurrent desensitization therapy, general anesthesia, advanced age, arterial hypotension, type 1 diabetes, aortic stenosis, mitral stenosis, acute myocardial infarction (after first 28 days).

Pregnancy and Breastfeeding

Pregnancy and Breastfeeding

Amlodipine:

Fetotoxic and embryotoxic effects of the drug have not been established in experimental studies, but use in pregnancy is possible only when the benefit to the mother exceeds the potential risk to the fetus. There are no data indicating excretion of amlodipine with breast milk. However, other DMARDs, dihydropyridine derivatives, are known to be excreted with breast milk. Therefore, if it is necessary to prescribe amlodipine during lactation, discontinuation of breastfeeding should be considered.

On bisoprolol:

The use of bisoprolol in pregnancy is possible only when the anticipated benefit to the mother outweighs the potential risk to the fetus. Beta-adrenoblockers reduce blood flow to the placenta and may affect fetal development.

The 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 taken if there are adverse events in relation to pregnancy and/or fetus. The newborn should be carefully examined after delivery. In the first three days of life, symptoms of bradycardia and hypoglycemia may occur.

There is no data on the excretion of bisoprolol into breast milk. Therefore, its intake is not recommended for women while breastfeeding. If bisoprolol administration during lactation is necessary, breastfeeding should be stopped.

Side effects

Unwanted adverse reactions observed when using the active ingredients separately are presented according to the following frequency grouping criteria:

Very frequent >1/10; frequent >1/100 to <1/10; infrequent >1/1 LLC to <1/100; rare a 1/10 000 to <1/1 LLC; very rare (<1/10 000), unknown (assessment based on available data cannot be performed). On amlodipine:

Blood and lymphatic system disorders: very rare – leukopenia, thrombocytopenia.

Immune system disorders: very rare – allergic reactions.

Metabolism and nutrition disorders: very rare – hyperglycemia.

Psychiatric disorders: infrequent – insomnia, mood changes (including anxiety), depression; rarely – mental confusion.

Nervous system disorders: frequently – headache, dizziness, somnolence (especially at the beginning of treatment); infrequent – syncope, hypoesthesia, paresthesia, dysgeusia, tremor; very rarely – muscle hypertonia, peripheral neuropathy;

VIight disorders: infrequent – visual disturbances (including diplopia).including diplopia).

Hearing and labyrinth disorders: infrequent – tinnitus.

Gastro-intestinal disorders: frequently – nausea, abdominal pain; infrequent – vomiting, change of defecation mode (including constipation or diarrhea); dyspepsia, dry mouth; very rarely – gastritis, gum hyperplasia, pancreatitis. Liver and biliary tract disorders: very rare – hepatitis *, jaundice *.

Chronic disorders: often – feeling of palpitation; very rarely – myocardial infarction, arrhythmia (bradycardia, ventricular tachycardia, atrial fibrillation).

Vascular disorders: frequently: “flushes” of blood to the face, rarely – marked decrease in blood pressure; very rarely – vasculitis. Respiratory system disorders, thoracic and mediastinal organs: infrequent – shortness of breath, rhinitis; very rare – cough. Renal and urinary tract disorders: infrequent – pollakiuria, painful urge to urinate, nycturia. Genital and breast disorders: infrequent – impotence, gynecomastia.

General disorders and disorders at the site of administration: frequently – peripheral edema, increased fatigue; infrequently – chest pain, asthenia, pain, general malaise.

Muscular and connective tissue disorders: frequently – edema of the ankles; infrequently – arthralgia, myalgia, muscle cramps, back pain.

Skin and subcutaneous skin disorders: infrequent – 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: infrequent – weight gain, weight loss; very rare – increase of “liver” enzymes activity*.

*In most cases with cholestasis Po bisoprolol;

Metabolic and nutritional disorders: rare – increase in triglyceride concentration.

Psychiatric disorders: infrequent – depression; rare – hallucinations, nightmares.

Nervous system disorders: often – headache, dizziness; infrequent – insomnia; rarely – fainting. Eye disorders: rare – decreased lacrimation (should be considered when wearing contact lenses); very rare – conjunctivitis.

Hearing organ and labyrinth disorders: rare – hearing disorders.

Chronic disorders: infrequent – AV conduction disorders, bradycardia, worsening of CHF symptoms. Vascular disorders: frequently – sensation of cold or numbness in extremities, marked BP decrease; rarely – orthostatic hypotension.

Respiratory system disorders, thoracic and mediastinal organs: infrequent – bronchospasm in patients with bronchial asthma or airway obstruction in anamnesis; rarely – allergic rhinitis.

Gastrointestinal disorders: frequently: nausea, vomiting, diarrhea, constipation.

Disorders of the liver and biliary tract: rarely – hepatitis.

Skin and subcutaneous skin disorders: rare – hypersensitivity reactions such as skin itching, rash, skin hyperemia; very rare – alopecia. Beta-adrenoblockers may contribute to exacerbation of psoriasis symptoms or cause psoriasis-like rash.

Musculoskeletal and connective tissue disorders: infrequent – muscle weakness, muscle cramps.

Disorders of the genitals and the mammary gland: rarely – impotence.

General disorders and disorders at the site of administration: often – increased fatigue”; infrequently – exhaustion**.

Laboratory and instrumental data rarely – increased activity of “hepatic” transaminases in the blood (aspartate aminotransferase (ACT), alanine aminotransferase (ALT)).

** These symptoms are especially common at the beginning of treatment. Usually these phenomena are mild and usually go away within 1-2 weeks after the start of treatment.

Overdose

Ampopin;

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

The treatment: gastric lavage, administration of activated charcoal, maintenance of cardiovascular function, control of heart and lung function parameters, elevated extremities, control of circulating blood volume and diuresis. Intensive symptomatic therapy. To restore vascular tone – the use of vasoconstrictors (if there are no contraindications for their use); to eliminate the effects of calcium channel blockade – intravenous injection of calcium gluconate. Hemodialysis is not effective.

On bisoprolol;

Symptoms: AV blockade, marked bradycardia; marked BP decrease, bronchospasm, acute heart failure, and hypoglycemia.

The sensitivity to single high-dose bisoprolol administration varies widely among individual patients, and it is likely that patients with CHF have a high sensitivity.

Treatment: If there is an overdose, the first step is to stop taking the drug and begin supportive symptomatic therapy.

In case of severe bradycardia: intravenous injection of atropine. If the effect is insufficient, a drug with positive chronotropic action may be administered with caution. Sometimes a temporary artificial pacemaker may be needed. With a marked decrease in BP: intravenous administration of plasma substitute solutions and vasopressor drugs. Intravenous administration of glucagon may also be indicated.

In AV blockade: patients should be under constant supervision, and receive treatment with beta-adrenomimetics, such as epinephrine. If necessary, placement of an artificial pacemaker.

In exacerbation of CHF: intravenous administration of diuretics, drugs with positive inotropic effect, and vasodilators.

In case of bronchospasm: administration of bronchodilators, including beta2-adrenomimetics and/or aminophylline.